Help Me Understand Genetics

Reprinted from MedlinePlus Genetics

U.S. National Library of Medicine

National Institutes of Health

Department of Health & Human Services

 Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/)

CONTENTS

1 Cells and DNA 1

1.1 What is a cell? 1
1.2 What is DNA? 6
1.3 What is a gene? 9
1.4 What is a chromosome? 11
1.5 How many chromosomes do people have? 13
1.6 What is noncoding DNA? 15

2 How Genes Work 17

2.1 What are proteins and what do they do? 17
2.2 How do genes direct the production of proteins? 21
2.3 Can genes be turned on and off in cells? 23
2.4 What is epigenetics? 24
2.5 How do cells divide? 26
2.6 How do genes control the growth and division of cells? 28
2.7 How do geneticists indicate the location of a gene? 32

3 Variants and Health 35

3.1 What is a gene variant and how do variants occur? 35
3.2 How can gene variants affect health and development? 37
3.3 Do all gene variants affect health and development? 38
3.4 What kinds of gene variants are possible? 40
3.5 Can a change in the number of genes affect health and development? 46
3.6 Can changes in the number of chromosomes affect health and
development? 47
3.7 Can changes in the structure of chromosomes affect health and
development? 53
3.8 Can changes in noncoding DNA affect health and development? 60
3.9 Can changes in mitochondrial DNA affect health and development? 62

i
 3.10 What are complex or multifactorial disorders? 63
3.11 What does it mean to have a genetic predisposition to a disease? 64
3.12 How are gene variants involved in evolution? 66
3.13 What information can statistics provide about a genetic condition? 68
3.14 How are genetic conditions and genes named? 70

4 Inheriting Genetic Conditions 72

4.1 What does it mean if a disorder seems to run in my family? 72
4.2 Why is it important to know my family health history? 74
4.3 What are the different ways a genetic condition can be inherited? 76
4.4 If a genetic disorder runs in my family, what are the chances that my
children will have the condition? 85
4.5 What are reduced penetrance and variable expressivity? 88
4.6 What do geneticists mean by anticipation? 89
4.7 What are genomic imprinting and uniparental disomy? 90
4.8 Are chromosomal disorders inherited? 92
4.9 Why are some genetic conditions more common in particular ethnic
groups? 93
4.10 What is heritability? 94

5 Genetics and Human Traits 96

5.1 Are fingerprints determined by genetics? 96
5.2 Is eye color determined by genetics? 98
5.3 Is intelligence determined by genetics? 102
5.4 Is handedness determined by genetics? 104
5.5 Is the probability of having twins determined by genetics? 106
5.6 Is hair texture determined by genetics? 108
5.7 Is hair color determined by genetics? 110
5.8 Is height determined by genetics? 113
5.9 Are moles determined by genetics? 115
5.10 Are facial dimples determined by genetics? 117
5.11 Is athletic performance determined by genetics? 118
5.12 Is longevity determined by genetics? 120
5.13 Is temperament determined by genetics? 123

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6 Genetic Consultation 125
6.1 What is a genetic consultation? 125
6.2 Why might someone have a genetic consultation? 126
6.3 What happens during a genetic consultation? 127
6.4 How can I find a genetics professional in my area? 128
6.5 What is the prognosis of a genetic condition? 129
6.6 How are genetic conditions diagnosed? 131
6.7 How are genetic conditions treated or managed? 133

7 Genetic Testing 135

7.1 What is genetic testing? 135
7.2 What are the different types of genetic tests? 137
7.3 What are the uses of genetic testing? 140
7.4 How is genetic testing done? 142
7.5 What is informed consent? 143
7.6 How can I be sure a genetic test is valid and useful? 145
7.7 What do the results of genetic tests mean? 147
7.8 What is the cost of genetic testing, and how long does it take to get the
results? 149
7.9 Will health insurance cover the costs of genetic testing? 150
7.10 What are the benefits of genetic testing? 151
7.11 What are the risks and limitations of genetic testing? 152
7.12 What is genetic discrimination? 153
7.13 Can genes be patented? 154
7.14 How are genetic screening tests different from genetic diagnostic tests? 155
7.15 How does genetic testing in a research setting differ from clinical genetic
testing? 157
7.16 What are whole exome sequencing and whole genome sequencing? 158
7.17 What are secondary findings from genetic testing? 160
7.18 What is noninvasive prenatal testing (NIPT) and what disorders can it
screen for? 163
7.19 What is circulating tumor DNA and how is it used to diagnose and
manage cancer? 166

8 Direct-to-Consumer Genetic Testing 169

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 8.1 What is direct-to-consumer genetic testing? 169
8.2 What kinds of direct-to-consumer genetic tests are available? 171
8.3 What is genetic ancestry testing? 173
8.4 What are the benefits and risks of direct-to-consumer genetic testing? 175
8.5 How do I choose a direct-to-consumer genetic testing company? 177
8.6 How is direct-to-consumer genetic testing done? 179
8.7 How much does direct-to-consumer genetic testing cost, and is it covered
by health insurance? 180
8.8 What do the results of direct-to-consumer genetic testing mean? 181
8.9 What can raw data from a direct-to-consumer genetic test tell me? 183
8.10 Can a direct-to-consumer genetic test tell me whether I will develop
cancer? 184
8.11 Can a direct-to-consumer genetic test tell me whether I will develop
Alzheimer's disease? 186
8.12 What does it mean to have Neanderthal or Denisovan DNA? 188
8.13 How do direct-to-consumer genetic testing companies protect their
customers’ privacy? 190
8.14 Can the results of direct-to-consumer genetic testing affect my ability to
get insurance? 192
8.15 Where can I read more about the diseases and traits covered in my direct-
to-consumer genetic testing report? 193

9 Gene Therapy and Other Medical Advances 196

9.1 What is gene therapy? 196
9.2 How does gene therapy work? 198
9.3 Is gene therapy safe? 201
9.4 What are the ethical issues surrounding gene therapy? 203
9.5 Is gene therapy available to treat my disorder? 204
9.6 What are CAR T cell therapy, RNA therapy, and other genetic therapies? 205
9.7 What are mRNA vaccines and how do they work? 207

10 Genomic Research 209

10.1 What are single nucleotide polymorphisms (SNPs)? 209
10.2 What are genome-wide association studies? 210
10.3 What is pharmacogenomics? 211
10.4 What are genome editing and CRISPR-Cas9? 213

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11 Precision Medicine 216
11.1 What is precision medicine? 216
11.2 What is the difference between precision medicine and personalized
medicine? What about pharmacogenomics? 217
11.3 What is the Precision Medicine Initiative? 218
11.4 What are some potential benefits of precision medicine and the Precision
Medicine Initiative? 219
11.5 What are some of the challenges facing precision medicine and the
Precision Medicine Initiative? 221

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 1
Cells and DNA
1.1 What is a cell?
Cells are the basic building blocks of all living things. The human body is composed of
trillions of cells. They provide structure for the body, take in nutrients from food, convert
those nutrients into energy, and carry out specialized functions. Cells also contain the
body’s hereditary material and can make copies of themselves.

Cells have many parts, each with a different function. Some of these parts, called
organelles, are specialized structures that perform certain tasks within the cell. Human
cells contain the following major parts, listed in alphabetical order:

Cytoplasm
Within cells, the cytoplasm (Figure 1.1) is made up of a jelly-like fluid (called the cytosol)
and other structures that surround the nucleus.

FIGURE 1.1: The cytoplasm is fluid within cells that surrounds the nucleus.

Cytoskeleton
The cytoskeleton is a network of long fibers that make up the cell’s structural framework.
The cytoskeleton has several critical functions, including determining cell shape,
participating in cell division, and allowing cells to move. It also provides a track-like
system that directs the movement of organelles and other substances within cells.

Endoplasmic reticulum (ER)

This organelle helps process molecules created by the cell. The endoplasmic reticulum
(Figure 1.2) also transports these molecules to their specific destinations either inside or

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outside the cell.

FIGURE 1.2: The endoplasmic reticulum is a structure near the cell

nucleus.

Golgi apparatus
The Golgi apparatus (Figure 1.3) packages molecules processed by the endoplasmic
reticulum to be transported out of the cell.

FIGURE 1.3: The Golgi apparatus is a structure in the cell cytoplasm.

Lysosomes and peroxisomes

These organelles (Figure 1.4) are the recycling center of the cell. They digest foreign
bacteria that invade the cell, rid the cell of toxic substances, and recycle worn-out cell
components.

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 FIGURE 1.4: Lyosomes are cell structures in the cytoplasm.

Mitochondria
Mitochondria (Figure 1.5) are complex organelles that convert energy from food into a
form that the cell can use. They have their own genetic material, separate from the DNA
in the nucleus, and can make copies of themselves.

FIGURE 1.5: Mitochondria are structures within the cell cytoplasm.

Nucleus
The nucleus serves as the cell’s command center, sending directions to the cell to grow,
mature, divide, or die. It also houses DNA (deoxyribonucleic acid), the cell’s hereditary
material. The nucleus is surrounded by a membrane called the nuclear envelope, which
protects the DNA and separates the nucleus from the rest of the cell.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 3

Plasma membrane
The plasma membrane (Figure 1.6) is the outer lining of the cell. It separates the cell
from its environment and allows materials to enter and leave the cell.

FIGURE 1.6: The plasma membrane surrounds a cell.

Ribosomes
Ribosomes (Figure 1.7) are organelles that process the cell’s genetic instructions to
create proteins. These organelles can float freely in the cytoplasm or be connected to
the endoplasmic reticulum (see above).

FIGURE 1.7: Ribosomes are cell structures near the nucleus.

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For more information about cells:
The National Institute of General Medical Sciences has a science education booklet
about cells called Inside the Cell (https://www.nigms.nih.gov/education/Booklets/Inside-t
he-Cell/Pages/Home.aspx).

The National Human Genome Research Institute's Talking Glossary (https://www.geno

me.gov/genetics-glossary/Cell) provides a definition of a cell as well as an illustration
and video.

The Genetic Science Learning Center at the University of Utah offers an interactive
introduction to cells (https://learn.genetics.utah.edu/content/cells/insideacell/) and their
many functions.

Arizona State University's "Ask a Biologist" provides a description and illustration of

each of the cell’s organelles (https://askabiologist.asu.edu/cell-parts).

Queen Mary University of London allows you to explore a 3-D cell and its parts (https://
www.centreofthecell.org/learn-play/games/explore-a-cell/).

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 1.2 What is DNA?
DNA, or deoxyribonucleic acid, is the hereditary material in humans and almost all other
organisms. Nearly every cell in a person’s body has the same DNA. Most DNA is
located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA
can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA).
Mitochondria (Figure 1.5) are structures within cells that convert the energy from food
into a form that cells can use.

The information in DNA is stored as a code made up of four chemical bases: adenine (A)
, guanine (G), cytosine (C), and thymine (T). Human DNA consists of about 3 billion
bases, and more than 99 percent of those bases are the same in all people. The order,
or sequence, of these bases determines the information available for building and
maintaining an organism, similar to the way in which letters of the alphabet appear in a
certain order to form words and sentences.

DNA bases pair up with each other, A with T and C with G, to form units called base
pairs. Each base is also attached to a sugar molecule and a phosphate molecule.
Together, a base, sugar, and phosphate are called a nucleotide. Nucleotides are
arranged in two long strands that form a spiral called a double helix. The structure of the
double helix is somewhat like a ladder, with the base pairs forming the ladder’s rungs
and the sugar and phosphate molecules forming the vertical sidepieces of the ladder.

An important property of DNA is that it can replicate, or make copies of itself. Each
strand of DNA in the double helix can serve as a pattern for duplicating the sequence of
bases. This is critical when cells divide because each new cell needs to have an exact
copy of the DNA present in the old cell.

DNA is a double helix formed by base pairs attached to a sugar-phosphate backbone.

(Figure 1.8)

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 FIGURE 1.8: DNA is made up of base pairs and a sugar phosphate
backbone.

For more information about DNA:

The National Human Genome Research Institute (NHGRI), a part of the National
Institutes of Health (NIH), provides a fact sheet Deoxyribonucleic Acid (DNA) (https://ww
w.genome.gov/about-genomics/fact-sheets/Deoxyribonucleic-Acid-Fact-Sheet) that
gives an introduction to this molecule.

StatedClearly offers a video introduction to DNA and how it works (https://www.statedcl

early.com/videos/what-is-dna/).

The New Genetics, a publication of the National Institute of General Medical Sciences,
part of the NIH, discusses the structure of DNA and how it was discovered (https://www.
nigms.nih.gov/education/Booklets/the-new-genetics/Pages/Home.aspx).

A basic explanation and illustration of DNA (https://askabiologist.asu.edu/dna-shape-an

d-structure) can be found on Arizona State University's "Ask a Biologist" website.

The Virtual Genetics Education Centre, created by the University of Leicester, offers

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additional information on DNA, genes, and chromosomes (https://www2.le.ac.uk/projects/vg
ec/highereducation/topics/dna-genes-chromosomes).

An overview of mitochondrial DNA (https://neuromuscular.wustl.edu/mitosyn.html#gener

al) is available from the Neuromuscular Disease Center at Washington University in St.
Louis.

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 1.3 What is a gene?
A gene is the basic physical and functional unit of heredity. Genes are made up of DNA.
Some genes act as instructions to make molecules called proteins. However, many
genes do not code for proteins. In humans, genes vary in size from a few hundred DNA
bases to more than 2 million bases. An international research effort called the Human
Genome Project, which worked to determine the sequence of the human genome and
identify the genes that it contains, estimated that humans have between 20,000 and 25,
000 genes.

Every person has two copies of each gene, one inherited from each parent. Most genes
are the same in all people, but a small number of genes (less than 1 percent of the total)
are slightly different between people. Alleles are forms of the same gene with small
differences in their sequence of DNA bases. These small differences contribute to each
person’s unique physical features.

Scientists keep track of genes by giving them unique names. Because gene names can
be long, genes are also assigned symbols, which are short combinations of letters (and
sometimes numbers) that represent an abbreviated version of the gene name. For
example, a gene on chromosome 7 that has been associated with cystic fibrosis is
called the cystic fibrosis transmembrane conductance regulator; its symbol is CFTR.

Genes are made up of DNA. Each chromosome contains many genes. (Figure 1.9)

FIGURE 1.9: A gene is labeled along the length of a chromosome.

For more information about genes:

MedlinePlus Genetics provides consumer-friendly gene summaries (https://medlineplus.
gov/genetics/gene/) that include an explanation of each gene's normal function and how
variants in the gene cause particular genetic conditions.

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More information about how genetic conditions and genes are named (https://medlinepl
us.gov/genetics/understanding/mutationsanddisorders/naming/) is also available from
MedlinePlus Genetics.

The Centre for Genetics Education offers a fact sheet that introduces genes and
chromosomes (https://www.genetics.edu.au/SitePages/DNA-RNA-genes-and-chromoso
mes.aspx).

The Tech Museum of Innovation at Stanford University describes genes and how they
were discovered (https://genetics.thetech.org/about-genetics/what-gene).

The Virtual Genetics Education Centre, created by the University of Leicester, offers
additional information on DNA, genes, and chromosomes (https://www2.le.ac.uk/project
s/vgec/highereducation/topics/dna-genes-chromosomes).

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 1.4 What is a chromosome?
In the nucleus of each cell, the DNA molecule is packaged into thread-like structures
called chromosomes. Each chromosome is made up of DNA tightly coiled many times
around proteins called histones that support its structure.

Chromosomes are not visible in the cell’s nucleus—not even under a microscope—
when the cell is not dividing. However, the DNA that makes up chromosomes becomes
more tightly packed during cell division and is then visible under a microscope. Most of
what researchers know about chromosomes was learned by observing chromosomes
during cell division.

Each chromosome has a constriction point called the centromere, which divides the
chromosome into two sections, or “arms.” The short arm of the chromosome is labeled
the “p arm.” The long arm of the chromosome is labeled the “q arm.” The location of the
centromere on each chromosome gives the chromosome its characteristic shape, and
can be used to help describe the location of specific genes.

DNA and histone proteins are packaged into structures called chromosomes. (Figure 1.
10)

FIGURE 1.10: Chromosomes have a p arm, a q arm, and a centromere.

They are made up of DNA wrapped around histone proteins.

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For more information about chromosomes:
MedlinePlus Genetics provides information about each human chromosome (https://me
dlineplus.gov/genetics/chromosome/) written in lay language.

A basic introduction to chromosomes (https://www.genome.gov/about-genomics/fact-sh

eets/Chromosomes-Fact-Sheet) is available from the National Human Genome
Research Institute.

The Centre for Genetics Education offers a fact sheet that introduces genes and
chromosomes (https://www.genetics.edu.au/SitePages/DNA-RNA-genes-and-chromoso
mes.aspx).

The University of Utah's Genetic Science Learning Center offers a description of

chromosomes (https://learn.genetics.utah.edu/content/basics/readchromosomes/),
including how scientists tell them apart.

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 1.5 How many chromosomes do people have?
In humans, each cell normally contains 23 pairs of chromosomes, for a total of 46.
Twenty-two of these pairs, called autosomes, look the same in both males and females.
The 23rd pair, the sex chromosomes, differ between males and females. Females have
two copies of the X chromosome, while males have one X and one Y chromosome.

The 22 autosomes are numbered by size. The other two chromosomes, X and Y, are
the sex chromosomes. This picture of the human chromosomes lined up in pairs is
called a karyotype. (Figure 1.11)

FIGURE 1.11: A normal male karyotype

with 22 autosomes, one X chromosome, and one Y chromosome.

For more information about the 23 pairs of human chromosomes:

MedlinePlus Genetics provides information about each human chromosome (https://me
dlineplus.gov/genetics/chromosome/) written in lay language.

MedlinePlus offers additional details about karyotype genetic tests (https://medlineplus.

gov/lab-tests/karyotype-genetic-test/).

The University of Utah's Genetic Science Learning Center discusses how karyotypes
can be used in diagnosing genetic disorders (https://learn.genetics.utah.edu/content/bas
ics/diagnose/).

Arizona State University's "Ask a Biologist" discusses the inheritance of human

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chromosomes. (https://askabiologist.asu.edu/chromosomes-and-genes)

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 1.6 What is noncoding DNA?
Only about 1 percent of DNA is made up of protein-coding genes; the other 99 percent
is noncoding. Noncoding DNA does not provide instructions for making proteins.
Scientists once thought noncoding DNA was “junk,” with no known purpose. However, it
is becoming clear that at least some of it is integral to the function of cells, particularly
the control of gene activity. For example, noncoding DNA contains sequences that act
as regulatory elements, determining when and where genes are turned on and off. Such
elements provide sites for specialized proteins (called transcription factors) to attach
(bind) and either activate or repress the process by which the information from genes is
turned into proteins (transcription). Noncoding DNA contains many types of regulatory
elements:
• Promoters provide binding sites for the protein machinery that carries out
transcription. Promoters are typically found just ahead of the gene on the DNA
strand.
• Enhancers provide binding sites for proteins that help activate transcription.
Enhancers can be found on the DNA strand before or after the gene they control,
sometimes far away.
• Silencers provide binding sites for proteins that repress transcription. Like
enhancers, silencers can be found before or after the gene they control and can be
some distance away on the DNA strand.
• Insulators provide binding sites for proteins that control transcription in a number of
ways. Some prevent enhancers from aiding in transcription (enhancer-blocker
insulators). Others prevent structural changes in the DNA that repress gene activity
(barrier insulators). Some insulators can function as both an enhancer blocker and a
barrier.

Other regions of noncoding DNA provide instructions for the formation of certain kinds
of RNA molecules. RNA is a chemical cousin of DNA. Examples of specialized RNA
molecules produced from noncoding DNA include transfer RNAs (tRNAs) and ribosomal
RNAs (rRNAs), which help assemble protein building blocks (amino acids) into a chain
that forms a protein; microRNAs (miRNAs), which are short lengths of RNA that block
the process of protein production; and long noncoding RNAs (lncRNAs), which are
longer lengths of RNA that have diverse roles in regulating gene activity.

Some structural elements of chromosomes are also part of noncoding DNA. For
example, repeated noncoding DNA sequences at the ends of chromosomes form
telomeres. Telomeres protect the ends of chromosomes from being degraded during
the copying of genetic material. Repetitive noncoding DNA sequences also form
satellite DNA, which is a part of other structural elements. Satellite DNA is the basis of
the centromere, which is the constriction point of the X-shaped chromosome pair.
Satellite DNA also forms heterochromatin, which is densely packed DNA that is
important for controlling gene activity and maintaining the structure of chromosomes.

Some noncoding DNA regions, called introns, are located within protein-coding genes
but are removed before a protein is made. Regulatory elements, such as enhancers,

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can be located in introns. Other noncoding regions are found between genes and are
known as intergenic regions.

The identity of regulatory elements and other functional regions in noncoding DNA is not
completely understood. Researchers are working to understand the location and role of
these genetic components.

Scientific journal articles for further reading

Maston GA, Evans SK, Green MR. Transcriptional regulatory elements in the human
genome. Annu Rev Genomics Hum Genet. 2006;7:29-59. Review. PubMed: 16719718.

ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the

human genome. Nature. 2012 Sep 6;489(7414):57-74. doi: 10.1038/nature11247.
PubMed: 22955616; Free full text available from PubMed Central: PMC3439153.

Plank JL, Dean A. Enhancer function: mechanistic and genome-wide insights come
together. Mol Cell. 2014 Jul 3;55(1):5-14. doi: 10.1016/j.molcel.2014.06.015. Review.
PubMed: 24996062.

For more information about noncoding DNA:

Cold Spring Harbor Laboratory DNA Learning Center: The Human Genome: Genes and
Non-coding DNA, 3D Animation with Basic Narration (https://dnalc.cshl.edu/view/15486-
The-human-genome-genes-and-non-coding-DNA-3D-animation-with-basic-narration.ht
ml)

University of Leicester Virtual Genetics Education Centre: Gene Expression and

Regulation (https://www2.le.ac.uk/projects/vgec/highereducation/topics/geneexpression-
regulation)

National Academies Press: Noncoding DNA—Subtlety, Punctuation, or Just Plain Junk?

(https://www.nap.edu/read/1859/chapter/6#99)

Khan Academy: Transcription Factors (https://www.khanacademy.org/science/biology/g

ene-regulation/gene-regulation-in-eukaryotes/a/eukaryotic-transcription-factors)

The Cell: A Molecular Approach (second edition, 2000): Regulation of Transcription in

Eukaryotes (https://www.ncbi.nlm.nih.gov/books/NBK9904/)

Genetic Science Learning Center, University of Utah: RNA’s Role in the Central Dogma
(https://learn.genetics.utah.edu/content/basics/centraldogma/), Telomeres (https://learn.
genetics.utah.edu/content/basics/telomeres/), and Centromeres (https://learn.genetics.u
tah.edu/content/basics/readchromosomes/)

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 2
How Genes Work
2.1 What are proteins and what do they do?
Proteins are large, complex molecules that play many critical roles in the body. They do
most of the work in cells and are required for the structure, function, and regulation of
the body’s tissues and organs.

Proteins are made up of hundreds or thousands of smaller units called amino acids,
which are attached to one another in long chains. There are 20 different types of amino
acids that can be combined to make a protein. The sequence of amino acids
determines each protein’s unique 3-dimensional structure and its specific function.
Amino acids are coded by combinations of three DNA building blocks (nucleotides),
determined by the sequence of genes.

Proteins can be described according to their large range of functions in the body, listed
in alphabetical order:

Antibody. Antibodies bind to specific foreign particles, such as viruses and bacteria, to
help protect the body.
Example: Immunoglobulin G (IgG) (Figure 2.1)

Enzyme. Enzymes carry out almost all of the thousands of chemical reactions that take
place in cells. They also assist with the formation of new molecules by reading the
genetic information stored in DNA.
Example: Phenylalanine hydroxylase (Figure 2.2)

Messenger. Messenger proteins, such as some types of hormones, transmit signals to

coordinate biological processes between different cells, tissues, and organs.
Example: Growth hormone (Figure 2.3)

Structural component. These proteins provide structure and support for cells. On a
larger scale, they also allow the body to move.
Example: Actin (Figure 2.4)

Transport/storage. These proteins bind and carry atoms and small molecules within
cells and throughout the body.
Example: Ferritin (Figure 2.5)

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FIGURE 2.1: The structure of immunoglobulin G, including foreign particle
binding sites.

FIGURE 2.2: The phenylalanine hydroxylase protein consists of four

subunits.

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FIGURE 2.3: The structure of growth hormone, and growth hormone bound
to its receptor.

FIGURE 2.4: An actin filament consisting of multiple subunits.

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 FIGURE 2.5: Ferritin protein consisting of 24 subunits.

For more information about proteins and their functions:

Arizona State University's "Ask a Biologist" discusses the different kinds of proteins (http
s://askabiologist.asu.edu/venom/what-are-proteins) and what they do.

The textbook Molecular Biology of the Cell (4th edition, 2002), from the NCBI Bookshelf,
offers a detailed introduction to protein function (https://www.ncbi.nlm.nih.gov/books/NB
K26911/).

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 2.2 How do genes direct the production of proteins?
Most genes contain the information needed to make functional molecules called
proteins. (A few genes produce regulatory molecules that help the cell assemble
proteins.) The journey from gene to protein is complex and tightly controlled within each
cell. It consists of two major steps: transcription and translation. Together, transcription
and translation are known as gene expression.

During the process of transcription, the information stored in a gene's DNA is passed to
a similar molecule called RNA (ribonucleic acid) in the cell nucleus. Both RNA and DNA
are made up of a chain of building blocks called nucleotides, but they have slightly
different chemical properties. The type of RNA that contains the information for making
a protein is called messenger RNA (mRNA) because it carries the information, or
message, from the DNA out of the nucleus into the cytoplasm.

Translation, the second step in getting from a gene to a protein, takes place in the
cytoplasm. The mRNA interacts with a specialized complex called a ribosome, which "
reads" the sequence of mRNA nucleotides. Each sequence of three nucleotides, called
a codon, usually codes for one particular amino acid. (Amino acids are the building
blocks of proteins.) A type of RNA called transfer RNA (tRNA) assembles the protein,
one amino acid at a time. Protein assembly continues until the ribosome encounters a “
stop” codon (a sequence of three nucleotides that does not code for an amino acid).

The flow of information from DNA to RNA to proteins is one of the fundamental
principles of molecular biology. It is so important that it is sometimes called the “central
dogma.”

Through the processes of transcription and translation, information from genes is used
to make proteins. (Figure 2.6)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 21

 FIGURE 2.6: DNA is transcribed into mRNA, which is transported into the
cell cytoplasm and translated into a protein.

For more information about making proteins:

The Genetic Science Learning Center at the University of Utah offers an interactive
introduction to transcription and translation (https://learn.genetics.utah.edu/content/basi
cs/dna).

The New Genetics (https://www.nigms.nih.gov/education/Booklets/the-new-genetics/Pa

ges/Home.aspx), a publication of the National Institute of General Medical Sciences,
includes discussions of transcription and translation.

Biointeractive from the Howard Hughes Medical Institute illustrates the stages in the
flow of information from DNA to RNA to protein. (https://www.biointeractive.org/classroo
m-resources/central-dogma-and-genetic-medicine) This tool also gives examples of
how modern technologies that target the different stages are used to treat genetic
diseases.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 22

 2.3 Can genes be turned on and off in cells?
Each cell expresses, or turns on, only a fraction of its genes at any given time. The rest
of the genes are repressed, or turned off. The process of turning genes on and off is
known as gene regulation. Gene regulation is an important part of normal development.
Genes are turned on and off in different patterns during development to make a brain
cell look and act different from a liver cell or a muscle cell, for example. Gene regulation
also allows cells to react quickly to changes in their environments. Although we know
that the regulation of genes is critical for life, this complex process is not yet fully
understood.

Gene regulation can occur at any point during gene expression, but most commonly
occurs at the level of transcription (when the information in a gene’s DNA is passed to
mRNA). Signals from the environment or from other cells activate proteins called
transcription factors. These proteins bind to regulatory regions of a gene and increase
or decrease the level of transcription. By controlling the level of transcription, this
process can determine when and how much protein product is made by a gene.

For more information about gene regulation:

The National Human Genome Research Institute provides a definition of gene
regulation (https://www.genome.gov/genetics-glossary/Gene-Regulation) in their Talking
Glossary of Genetic Terms.

The Genetic Science Learning Center at the University of Utah offers an explanation of
gene expression as it relates to disease risk (https://learn.genetics.utah.edu/content/sci
ence/expression/).

Additional information about gene expression (https://www.yourgenome.org/facts/what-i

s-gene-expression) is available from yourgenome.org, a service of the Wellcome Trust.

The Khan Academy has an educational unit on gene regulation (https://www.khanacade

my.org/science/biology/gene-regulation), including videos about gene regulation in
bacteria and eukaryotes.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 23

 2.4 What is epigenetics?
Epigenetics is the study of how cells control gene activity without changing the DNA
sequence."Epi-"means on or above in Greek,and "epigenetic" describes factors beyond
the genetic code. Epigenetic changes are modifications to DNA that regulate whether
genes are turned on or off. These modifications are attached to DNA and do not change
the sequence of DNA building blocks. Within the complete set of DNA in a cell (genome)
, all of the modifications that regulate the activity (expression) of the genes is known as
the epigenome.

Because epigenetic changes help determine whether genes are turned on or off, they
influence the production of proteins in cells. This regulation helps ensure that each cell
produces only proteins that are necessary for its function. For example, proteins that
promote bone growth are not produced in muscle cells. Patterns of epigenetic
modification vary among individuals, in different tissues within an individual, and even in
different cells within a tissue. Environmental influences, such as a person’s diet and
exposure to pollutants, can impact the epigenome. Epigenetic modifications can be
maintained from cell to cell as cells divide and, in some cases, can be inherited through
the generations.

A common type of epigenetic modification is called DNA methylation. DNA methylation

involves the attachment of small chemical groups called methyl groups (each consisting
of one carbon atom and three hydrogen atoms) to DNA building blocks. When methyl
groups are present on a gene, that gene is turned off or silenced, and no protein is
produced from that gene.

Another common epigenetic change is histone modification. Histones are structural

proteins in the cell nucleus. DNA wraps around histones, giving chromosomes their
shape. Histones can be modified by the addition or removal of chemical groups, such as
methyl groups or acetyl groups (each consisting of two carbon, three hydrogen, and one
oxygen atoms). The chemical groups influence how tightly the DNA is wrapped around
histones, which affects whether a gene can be turned on or off.

Errors in the epigenetic process, such as modification of the wrong gene or failure to
add a chemical group to a particular gene or histone, can lead to abnormal gene activity
or inactivity. Altered gene activity, including that caused by epigenetic errors, is a
common cause of genetic disorders. Conditions such as cancers, metabolic disorders,
and degenerative disorders have been found to be related to epigenetic errors.

Scientists continue to explore the relationship between the genome and the chemical
compounds that modify it. In particular, they are studying the effects that epigenetic
modifications and errors have on gene function, protein production, and human health.

For more information about the epigenome:

Human Epigenome Toolset (http://www.genboree.org/site/epigenomics_toolset) from
Baylor College of Medicine allows for comparison of the epigenomes of many species
and cell types.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 24

The University of Utah provides an interactive epigenetics tutorial (https://learn.genetics.
utah.edu/content/epigenetics/).

The National Human Genome Research Institute provides a fact sheet (https://www.gen
ome.gov/about-genomics/fact-sheets/Epigenomics-Fact-Sheet) on Epigenomics.

Many tools for understanding epigenomics are available through the NIH Common Fund
Epigenomics Project (https://commonfund.nih.gov/epigenomics/).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 25

 2.5 How do cells divide?
There are two types of cell division: mitosis and meiosis. Most of the time when people
refer to “cell division,” they mean mitosis, the process of making new body cells. Meiosis
is the type of cell division that creates egg and sperm cells.

Mitosis is a fundamental process for life. During mitosis, a cell duplicates all of its
contents, including its chromosomes, and splits to form two identical daughter cells.
Because this process is so critical, the steps of mitosis are carefully controlled by
certain genes. When mitosis is not regulated correctly, health problems such as cancer
can result.

The other type of cell division, meiosis, ensures that humans have the same number of
chromosomes in each generation. It is a two-step process that reduces the
chromosome number by half—from 46 to 23—to form sperm and egg cells. When the
sperm and egg cells unite at conception, each contributes 23 chromosomes so the
resulting embryo will have the usual 46. Meiosis also allows genetic variation through a
process of gene shuffling while the cells are dividing.

Mitosis and meiosis, the two types of cell division. (Figure 2.7)

FIGUR
E 2.7: The cell division processes of mitosis and meiosis.

For more information about cell division:

The National Human Genome Research Institute's Talking Glossary provides

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 26

information about mitosis (https://www.genome.gov/genetics-glossary/Mitosis) and meiosis (https://
www.genome.gov/genetics-glossary/Meiosis).

Yourgenome from the Wellcome Trust outlines the similarities and differences between
mitosis and meiosis (https://www.yourgenome.org/facts/mitosis-versus-meiosis).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 27

 2.6 How do genes control the growth and division of cells?
A variety of genes are involved in the control of cell growth and division. The cell
replicates itself in an organized, step-by-step fashion known as the cell cycle. Tight
regulation of this process ensures that a dividing cell’s DNA is copied properly, any
errors in the DNA are repaired, and each daughter cell receives a full set of
chromosomes. The cell cycle has checkpoints (also called restriction points), which
allow certain genes to check for problems and halt the cycle for repairs if something
goes wrong.

If a cell has an error in its DNA that cannot be repaired, it may undergo self-destruction
(apoptosis (Figure 2.8)). Apoptosis is a common process throughout life that helps the
body get rid of cells that no longer work or that it doesn’t need. Cells that undergo
apoptosis break apart (Figure 2.9) and are recycled by a type of white blood cell called
a macrophage. Apoptosis protects the body by removing genetically damaged cells that
could lead to cancer, and it plays an important role in the development of the embryo
and the maintenance of adult tissues.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 28

FIGURE 2.8: If a cell is unable to repair errors, it programs itself to die via
apoptosis.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 29

 FIGURE 2.9: A white blood cell and an apoptotic cell.

Disruption of normal regulation of the cell cycle can lead to diseases such as cancer.
When the cell cycle proceeds without control, cells can divide without order and
accumulate genetic errors that can lead to a cancerous tumor (Figure 2.10).

FIGURE 2.10: A tumor in the liver; inset shows the progression from a
normal cell to one in which genetic changes accumulate, leading to rapid

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 30

 and disorganized cell division.

For more information about cell growth and division:

The National Human Genome Research Institute's Talking Glossary provides

information about the cell cycle (https://www.genome.gov/genetics-glossary/Cell-Cycle).

The National Cancer Institute's fact sheet What is Cancer? (https://www.cancer.gov/abo

ut-cancer/understanding/what-is-cancer) explains the growth of cancerous tumors.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 31

 2.7 How do geneticists indicate the location of a gene?
Geneticists use maps to describe the location of a particular gene on a chromosome.
One type of map uses the cytogenetic location to describe a gene’s position. The
cytogenetic location is based on a distinctive pattern of bands created when
chromosomes are stained with certain chemicals. Another type of map uses the
molecular location, which is a precise description of a gene's position on a chromosome.
The molecular location is based on the sequence of DNA building blocks (nucleotides)
that make up the chromosome.

Cytogenetic location
Geneticists use a standardized way of describing a gene's cytogenetic location. In most
cases, the location describes the position of a particular band on a stained chromosome:

17q12

It can also be written as a range of bands, if less is known about the exact location:

17q12-q21

The combination of numbers and letters provide a gene's “address” on a chromosome.

This address is made up of several parts:
• The chromosome on which the gene can be found. The first number or letter used
to describe a gene's location represents the chromosome. Chromosomes 1 through
22 (the autosomes) are designated by their chromosome number. The sex
chromosomes are designated by X or Y.
• The arm of the chromosome. Each chromosome is divided into two sections (arms)
based on the location of a narrowing (constriction) called the centromere. By
convention, the shorter arm is called p, and the longer arm is called q. The
chromosome arm is the second part of the gene's address. For example, 5q is the
long arm of chromosome 5, and Xp is the short arm of the X chromosome.
• The position of the gene on the p or q arm. The position of a gene is based on a
distinctive pattern of light and dark bands that appear when the chromosome is
stained in a certain way. The position is usually designated by two digits
(representing a region and a band), which are sometimes followed by a decimal
point and one or more additional digits (representing sub-bands within a light or dark
area). The number indicating the gene position increases with distance from the
centromere. For example: 14q21 represents position 21 on the long arm of
chromosome 14. 14q21 is closer to the centromere than 14q22.

Sometimes, the abbreviations “cen” or “ter” are also used to describe a gene's
cytogenetic location. “Cen” indicates that the gene is very close to the centromere. For
example, 16pcen refers to the short arm of chromosome 16 near the centromere. “Ter”
stands for terminus, which indicates that the gene is very close to the end of the p or q

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 32

arm. For example, 14qter refers to the tip of the long arm, or the very end, of chromosome
14.

The CFTR gene is located on the long arm of chromosome 7 at position 7q31.2. (Figure
2.11)

FIGURE 2.11: The CFTR gene is located on the long (q) arm of
chromosome 7 at position 31.2.

Molecular location
The Human Genome Project, an international research effort completed in 2003,
determined the sequence of nucleotides for each human chromosome. This sequence
information allows researchers to provide a more specific address than the cytogenetic
location for many genes. A gene’s molecular address pinpoints the location of that gene
in terms of nucleotides. It describes the gene’s precise position on a chromosome and
indicates the size of the gene. Knowing the molecular location also allows researchers
to determine exactly how far a gene is from other genes on the same chromosome.

Different groups of researchers often present slightly different values for a gene’s
molecular location. Researchers interpret the sequence of the human genome using a
variety of methods, which can result in small differences in a gene’s molecular address.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 33

For more information on genetic mapping:
The National Human Genome Research Institute explains how researchers create a
genetic map (https://www.genome.gov/about-genomics/fact-sheets/Genetic-Mapping-Fa
ct-Sheet).

Information about assembling and annotating the genome (https://www.ncbi.nlm.nih.gov

/guide/genomes-maps/) is available from NCBI.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 34

 3
Variants and Health
3.1 What is a gene variant and how do variants occur?
A gene variant is a permanent change in the DNA sequence that makes up a gene. This
type of genetic change used to be known as a gene mutation, but because changes in
DNA do not always cause disease, it is thought that gene variant is a more accurate
term. Variants can affect one or more DNA building blocks (nucleotides) in a gene.

Gene variants can be inherited from a parent or occur during a person’s lifetime:
• Inherited (or hereditary) variants are passed from parent to child and are present
throughout a person’s life in virtually every cell in the body. These variants are also
called germline variants because they are present in the parent’s egg or sperm cells,
which are also called germ cells. When an egg and a sperm cell unite, the resulting
fertilized egg cell contains DNA from both parents. Any variants that are present in
that DNA will be present in the cells of the child that grows from the fertilized egg.
• Non-inherited variants occur at some time during a person’s life and are present
only in certain cells, not in every cell in the body. Because non-inherited variants
typically occur in somatic cells (cells other than sperm and egg cells), they are often
referred to as somatic variants. These variants cannot be passed to the next
generation. Non-inherited variants can be caused by environmental factors such as
ultraviolet radiation from the sun or can occur if an error is made as DNA copies
itself during cell division.

Some genetic changes are described as new (de novo) variants; these variants are
recognized in a child but not in either parent. In some cases, the variant occurs in a
parent’s egg or sperm cell but is not present in any of their other cells. In other cases,
the variant occurs in the fertilized egg shortly after the egg and sperm cells unite. (It is
often impossible to tell exactly when a de novo variant happened.) As the fertilized egg
divides, each resulting cell in the growing embryo will have the variant. De novo variants
are one explanation for genetic disorders in which an affected child has a variant in
every cell in the body, but the parents do not, and there is no family history of the
disorder.

Variants acquired during development can lead to a situation called mosaicism, in which
a set of cells in the body has a different genetic makeup than others. In mosaicism, the
genetic change is not present in a parent’s egg or sperm cells, or in the fertilized egg,
but happens later, anytime from embryonic development through adulthood. As cells
grow and divide, cells that arise from the cell with the altered gene will have the variant,
while other cells will not. When a proportion of somatic cells have a gene variant and
others do not, it is called somatic mosaicism. Depending on the variant and how many
cells are affected, somatic mosaicism may or may not cause health problems. When a
proportion of egg or sperm cells have a variant and others do not, it is called germline
mosaicism. In this situation, an unaffected parent can pass a genetic condition to their
child.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 35

Most variants do not lead to development of disease, and those that do are uncommon
in the general population. Some variants occur often enough in the population to be
considered common genetic variation. Several such variants are responsible for
differences between people such as eye color, hair color, and blood type. Although
many of these common variations in the DNA have no negative effects on a person’s
health, some may influence the risk of developing certain disorders.

For more information about variants:

The Centre for Genetics Education provides a fact sheet discussing variations in the
genetic code (https://www.genetics.edu.au/SitePages/Variations-in-the-Genetic-Code.a
spx).

An introductory explanation of what variants are and how they occur (https://www.yourg
enome.org/facts/what-is-a-mutation) is provided by Your Genome from the Wellcome
Genome Campus.

KidsHealth from Nemours offers an introduction to genes, genetics, and genetic

changes (https://kidshealth.org/en/parents/about-genetics.html).

Additional information about genetic alterations is available from the University of Utah
fact sheet "What is Mutation?" (https://learn.genetics.utah.edu/content/basics/mutation/)

Using animations and videos, DNA From the Beginning (Cold Spring Harbor National
Laboratory) describes the early experiments that helped researchers understand
genetic variants (http://www.dnaftb.org/27/).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 36

 3.2 How can gene variants affect health and development?
To function correctly, each cell depends on thousands of proteins to do their jobs in the
right places at the right times. Sometimes, gene variants (also known as mutations)
prevent one or more proteins from working properly. By changing a gene’s instructions
for making a protein, a variant can cause a protein to malfunction or to not be produced
at all. When a variant alters a protein that plays a critical role in the body, it can disrupt
normal development or cause a health condition. A condition caused by variants in one
or more genes is called a genetic disorder.

In some cases, gene variants are so severe that they prevent an embryo from surviving
until birth. These changes occur in genes that are essential for development, and often
disrupt the development of an embryo in its earliest stages. Because these variants
have very serious effects, they are incompatible with life.

It is important to note that genes themselves do not cause disease—genetic disorders

are caused by variants that alter or eliminate a gene’s function. For example, when
people say that someone has “the cystic fibrosis gene,” they are usually referring to a
version of the CFTR gene that contains a variant that causes the disease. All people,
including those without cystic fibrosis, have a version of the CFTR gene.

For more information about variants and genetic disorders:

The Genetic and Rare Diseases Information Center provides information to various
resources about genetic disorders (https://rarediseases.info.nih.gov/).

The Centre for Genetics Education offers a fact sheet about genetic changes that lead
to disorders (https://www.genetics.edu.au/SitePages/Types-of-Genetic-variation.aspx).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 37

 3.3 Do all gene variants affect health and development?
No; only a small percentage of variants cause genetic disorders—most have no impact
on health or development. For example, some variants alter a gene's DNA sequence
but do not change the function of the protein made from the gene.

Often, gene variants that could cause a genetic disorder are repaired by certain
enzymes before the gene is expressed and an altered protein is produced. Each cell
has a number of pathways through which enzymes recognize and repair errors in DNA.
Because DNA can be changed or damaged in many ways, DNA repair is an important
process by which the body protects itself from disease.

A very small percentage of all variants actually have a positive effect. These variants
lead to new versions of proteins that help an individual better adapt to changes in his or
her environment. For example, a beneficial variant could result in a protein that protects
an individual and future generations from a new strain of bacteria.

Because a person's genetic code can have many variants with no effect on health,
diagnosing genetic disorders can be difficult.

When determining if a gene variant is associated with a genetic disorder, the variant is
evaluated using scientific research to date, such as information on how the variant
affects the function or production of the protein that is made from the gene and previous
variant classification data. The variant is then classified on a spectrum based on how
likely the variant is to lead to the disorder.

Gene variants, as they relate to genetic disorders, are classified into one of five groups:
• Pathogenic: The variant is responsible for causing disease. There is ample scientific
research to support an association between the disease and the gene variant. These
variants are often referred to as mutations.
• Likely pathogenic: The variant is probably responsible for causing disease, but
there is not enough scientific research to be certain.
• Variant of uncertain significance (VUS or VOUS): The variant cannot be confirmed
to play a role in the development of disease. There may not be enough scientific
research to confirm or refute a disease association or the research may be
conflicting.
• Likely benign: The variant is probably not responsible for causing disease, but there
is not enough scientific research to be certain.
• Benign: The variant is not responsible for causing disease. There is ample scientific
research to disprove an association between the disease and the gene variant.

Evaluation needs to be done for each variant. Just because a gene is associated with a
disease, does not mean that all variants in that gene are pathogenic. Additionally,
evaluation of a variant needs to be done for all diseases with which it is thought to be
associated. A variant that is pathogenic for one disease, is not necessarily pathogenic
for a different disease. It is important to re-evaluate variants periodically; the

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 38

classification of a variant can change over time as more information about the effects of variants
becomes known through additional scientific research.

Scientific journal article for further reading

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M,
Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance
Committee. Standards and guidelines for the interpretation of sequence variants: a joint
consensus recommendation of the American College of Medical Genetics and
Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):
405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5. PMID: 25741868; PMCID:
PMC4544753.

For more information about the health effects of gene variants:

The University of Utah Genetic Science Learning Center provides information about
genetic disorders (https://learn.genetics.utah.edu/content/disorders/) that explains why
some variants cause disorders but others do not.

The National Human Genome Research Institute provides information about human
genomic variation (https://www.genome.gov/dna-day/15-ways/human-genomic-variation
).

Cold Spring Harbor National Laboratory’s DNA From the Beginning explains the
discovery of DNA repair mechanisms in cells (http://www.dnaftb.org/28/) and introduces
the researchers who worked to understand these mechanisms.

FORCE (Facing Our Risk of Cancer Empowered) explains the significance of variants of
unknown significance in cancer (https://www.facingourrisk.org/understanding-brca-and-
hboc/information/hereditary-cancer/genetic-testing/basics/variants-of-uncertain-significa
nce.php).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 39

 3.4 What kinds of gene variants are possible?
The DNA sequence of a gene can be altered in a number of ways. Gene variants (also
known as mutations) can have varying effects --on health, depending on where they
occur and whether they alter the function of essential proteins. Variant types include the
following:

Substitution

This type of variant replaces one DNA building block (nucleotide) with another.
Substitution variants can be further classified by the effect they have on the production
of protein from the altered gene.
• Missense: A missense variant (Figure 3.1) is a typeof substitution in which the
nucleotide change results in the replacement of one protein building block (amino
acid) with another in the protein made from the gene. The amino acid change may
alter the function of the protein.
• Nonsense: A nonsense variant (Figure 3.2) is another type of substitution. Instead
of causing a change in one amino acid, however, the altered DNA sequence results
in a stop signal that prematurely signals the cell to stop building a protein. This type
of variant results in a shortened protein that may function improperly, be
nonfunctional, or get broken down.

FIGURE 3.1: Replacement of a single nucleotide in the DNA sequence

creates an incorrect amino acid, which may result in a malfunctioning
protein.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 40

 FIGURE 3.2: Replacement of a single nucleotide leads to a stop codon,
which halts protein production at that point.

Insertion

An insertion (Figure 3.3) changes the DNA sequence by adding one or more
nucleotides to the gene. As a result, the protein made from the gene may not function
properly.

FIGURE 3.3: Insertion of a single nucleotide in the DNA sequence leads to

an incorrect sequence of amino acids, which may produce a malfunctioning

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 41

 protein.

Deletion

A deletion (Figure 3.4) changes the DNA sequence by removing at least one nucleotide
in a gene. Small deletions remove one or a few nucleotides within a gene, while larger
deletions can remove an entire gene or several neighboring genes. The deleted DNA
may alter the function of the affected protein or proteins.

FIGURE 3.4: The deletion of a single nucleotide leads to an incorrect

amino acid sequence, which may produce a malfunctioning protein.

Deletion-Insertion

This variant occurs when a deletion and insertion happen at the same time in the same
location in the gene. In a deletion-insertion variant, at least one nucleotide is removed
and at least one nucleotide is inserted. However, the change must be complex enough
to differ from a simple substitution. The resulting protein may not function properly. A
deletion-insertion (delins) variant may also be known as an insertion-deletion (indel)
variant.

Duplication

A duplication (Figure 3.5)occurs when a stretch of one or more nucleotides in a gene is

copied and repeated next to the original DNA sequence. This type of variant may alter
the function of the protein made from the gene.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 42

 FIGURE 3.5: A section of DNA from a chromosome is duplicated.

Inversion

An inversion changes more than one nucleotide in a gene by replacing the original
sequence with the same sequence in reverse order.

Frameshift

A reading frame consists of groups of three nucleotides that eachcode for one amino
acid. Aframeshift variant (Figure 3.6) occurs when there is an addition or loss of
nucleotides that shifts the grouping and changes the code for all downstream amino
acids. The resulting protein is usually nonfunctional. Insertions, deletions, and
duplications can all be frameshift variants.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 43

 FIGURE 3.6: A framshift of one DNA base results in an abnormal amino
acid sequence.

Repeat expansion

Some regions of DNA contain short sequences of nucleotides that are repeated a
number of times in a row. For example, a trinucleotide repeat is made up of sequences
of three nucleotides, and a tetranucleotide repeat is made up of sequences of four
nucleotides. Arepeat expansion (Figure 3.7) is a variant that increases the number of
times that the short DNA sequence is repeated. This type of variant can cause the
resulting protein to function improperly.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 44

 FIGURE 3.7: A trinucleotide (CAG) is repeated multiple times in a DNA
sequence, adding a string of glutamines to the protein.

For more information about the types of gene variants:

The National Human Genome Research Institute offers a Talking Glossary of Genetic
Terms (https://www.genome.gov/genetics-glossary). This resource includes definitions,
diagrams, and detailed audio descriptions of several of the gene variants listed above.

A brief explanation of different variants types (https://www.yourgenome.org/facts/what-ty

pes-of-mutation-are-there) is available from yourgenome.org, a service of the Wellcome
Trust.

The Khan Academy has a video describing the different types of gene variants (https://w
ww.khanacademy.org/test-prep/mcat/biomolecules/genetic-mutations/v/the-different-typ
es-of-mutations).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 45

 3.5 Can a change in the number of genes affect health and
development?
People have two copies of most genes, one copy inherited from each parent. In some
cases, however, the number of copies varies—meaning that a person can have one,
three, or more copies of particular genes. Less commonly, both copies of a gene may
be missing. These types of genetic difference are known as copy number variations
(CNV).

Copy number variation results from insertions, deletions, and duplications of large
segments of DNA that are at least one thousand nucleotides (also called 1 kilobase or
1kb) in length. These segments are often big enough to include whole genes. Variation
in gene copy number can influence the activity of genes and the functioning of proteins
made from them, which may affect body processes.

Copy number variation accounts for a significant amount of genetic difference between
people. More than 10 percent of the human genome appears to contain differences in
gene copy number. While much of this variation does not affect health or development,
some differences influence a person’s risk of disease, particularly some types of cancer,
or response to certain drugs.

For more information about copy number variation:

The Howard Hughes Medical Institute discusses the results of recent research on copy
number variation in the news release, Genetic Variation: We’re More Different Than We
Thought (https://www.hhmi.org/news/genetic-variation-were-more-different-we-thought).

More information about copy number variation (https://dnalc.cshl.edu/view/552-Copy-Nu

mber-Variants.html) is available in a video from Cold Spring Harbor Laboratory.

A definition of copy number variation (https://www.genome.gov/genetics-glossary/Copy-

Number-Variation) is included in the Talking Genome Glossary from the National
Human Genome Research Institute.

For people interested in more technical data, several institutions provide databases of
structural differences in human DNA, including copy number variation:
• The Centre for Applied Genomics Database of Genomic Variants (http://dgv.tcag.ca
/dgv/app/home)
• The Sanger Institute: Database of Chromosomal Imbalance and Phenotype in
Humans using Ensembl Resources (DECIPHER (https://decipher.sanger.ac.uk/))

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 46

 3.6 Can changes in the number of chromosomes affect
health and development?
Human cells normally contain 23 pairs of chromosomes, for a total of 46 chromosomes
in each cell (Figure 3.8). A change in the number of chromosomes can cause problems
with growth, development, and function of the body's systems. These changes can
occur during the formation of reproductive cells (eggs and sperm), in early fetal
development, or in any cell after birth. A gain or loss in the number of chromosomes
from the normal 46 is called aneuploidy.

FIGURE 3.8: Normal human karyotype with 22 pairs of autosomes and two
sex chromosomes, either two X chromosomes or an X and a Y
chromosome.

A common form of aneuploidy is trisomy, or the presence of an extra chromosome in

cells. "Tri-" is Greek for "three"; people with trisomy have three copies of a particular
chromosome in cells instead of the normal two copies. Down syndrome (also known as
trisomy 21) is an example of a condition caused by trisomy (Figure 3.9). People with
Down syndrome typically have three copies of chromosome 21 in each cell, for a total of
47 chromosomes per cell.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 47

 FIGURE 3.9: A karyotype showing an extra copy of chromsome 21, for a
total of 47 chromosomes instead of the usual 46.

Monosomy, or the loss of one chromosome in cells, is another kind of aneuploidy. "
Mono-" is Greek for "one"; people with monosomy have one copy of a particular
chromosome in cells instead of the normal two copies. Turner syndrome (also known as
monosomy X) is a condition caused by monosomy (Figure 3.10). Women with Turner
syndrome usually have only one copy of the X chromosome in every cell, for a total of
45 chromosomes per cell.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 48

 FIGURE 3.10: A karyotype showing a form of monosomy called Turner
syndrome, in which the second sex chromosome is missing.

Rarely, some cells end up with complete extra sets of chromosomes. Cells with one
additional set of chromosomes, for a total of 69 chromosomes, are called triploid (Figure
3.11). Cells with two additional sets of chromosomes, for a total of 92 chromosomes,
are called tetraploid. A condition in which every cell in the body has an extra set of
chromosomes is not compatible with life.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 49

 FIGURE 3.11: A karyotype with one extra copy of each chromosome, for a
total of 69 chromosomes instead of the usual 46.

In some cases, a change in the number of chromosomes occurs only in certain cells.
When an individual’s cells differ in their chromosomal makeup, it is known as
chromosomal mosaicism (Figure 3.12). Chromosomal mosaicism occurs from an error
in cell division in cells other than eggs and sperm. Most commonly, some cells end up
with one extra or missing chromosome (for a total of 45 or 47 chromosomes per cell),
while other cells have the usual 46 chromosomes. Mosaic Turner syndrome is one
example of chromosomal mosaicism. In females with this condition, some cells have 45
chromosomes because they are missing one copy of the X chromosome, while other
cells have the usual number of chromosomes.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 50

 FIGURE 3.12: A person with mosaicism has some populations of cells with
a chromsomal change and other cells without the change.

Many cancer cells also have changes in their number of chromosomes. These changes
are not inherited; they occur in somatic cells (cells other than eggs or sperm) during the
formation or progression of a cancerous tumor.

For more information about chromosomal disorders:

MedlinePlus provides a medical encyclopedia article about chromosomal mosaicism (htt
ps://medlineplus.gov/ency/article/001317.htm).

A discussion of how chromosomal abnormalities happen (https://www.genome.gov/abo

ut-genomics/fact-sheets/Chromosome-Abnormalities-Fact-Sheet) is provided by the
National Human Genome Research Institute.

The Centre for Genetics Education offers a fact sheet about changes in chromosome
number or size (https://www.genetics.edu.au/SitePages/Chromosome-changes.aspx).

The University of Leicester's Virtual Genetics Education Center provides an explanation

of numerical chromosome aberrations (https://www2.le.ac.uk/projects/vgec/healthprof/to
pics/patterns-of-inheritance/chromosomal-abnormalities#numerical-aberrations).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 51

Your Genome from the Wellcome Genome Campus discusses chromosome disorders (
https://www.yourgenome.org/facts/what-is-a-chromosome-disorder), including how
changes in the number of chromosomes cause genetic disorders.

The National Organization for Rare Disorders offers an overview of triploidy (https://rare
diseases.org/rare-diseases/triploidy/).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 52

 3.7 Can changes in the structure of chromosomes affect
health and development?
Changes that affect the structure of chromosomes can cause problems with growth,
development, and function of the body's systems. These changes can affect many
genes along the chromosome and disrupt the proteins made from those genes.

Structural changes can occur during the formation of egg or sperm cells, in early fetal
development, or in any cell after birth. Pieces of DNA can be rearranged within one
chromosome or transferred between two or more chromosomes. The effects of
structural changes depend on their size and location, whether gene function is
interrupted, and whether any genetic material is gained or lost. Some changes cause
health problems, while others may have no effect on a person's health.

Changes in chromosome structure include the following:

Translocations
A translocation occurs when a piece of one chromosome breaks off and attaches to
another chromosome. This type of rearrangement is described as balanced (Figure 3.13)
if no genetic material is gained or lost in the cell. If there is a gain or loss of genetic
material, the translocation is described as unbalanced (Figure 3.14).

FIGURE 3.13: Two chromosomes break and swap pieces; no genetic

material is gained or lost.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 53

 FIGURE 3.14: A balanced translocation can become unbalanced in the
next generation, with extra or missing genetic material.

Deletions
Deletions (Figure 3.15) occur when a chromosome breaks and some genetic material is
lost. Deletions can be large or small, and can occur anywhere along a chromosome.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 54

 FIGURE 3.15: Genetic material is deleted from a chromosome.

Duplications
Duplications (Figure 3.16) occur when part of a chromosome is abnormally copied
(duplicated). This type of chromosomal change results in extra copies of genetic
material from the duplicated segment.

FIGURE 3.16: DNA from a chromosome is abnormally copied.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 55

Inversions
An inversion (Figure 3.17) occurs when a chromosome breaks in two places; the
resulting piece of DNA is reversed and re-inserted into the chromosome. Genetic
material may or may not be lost as a result of the chromosome breaks. An inversion that
includes the chromosome's constriction point (centromere) is called a pericentric
inversion. An inversion that occurs in the long (q) arm or short (p) arm and does not
involve the centromere is called a paracentric inversion.

FIGURE 3.17: A paracentric inversion does not include the centromere; a

pericentric inversion does include the centromere.

Isochromosomes
An isochromosome (Figure 3.18) is a chromosome with two identical arms. Instead of
one q arm and one p arm, an isochromosome has two q arms or two p arms. As a result,
these abnormal chromosomes have an extra copy of some genes and are lacking
copies of genes on the missing arm.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 56

 FIGURE 3.18: Isochromosomes have two p arms or two q arms instead of
one p arm and one q arm.

Dicentric chromosomes
Unlike normal chromosomes, which have one centromere, a dicentric chromosome
(Figure 3.19) contains two centromeres. Dicentric chromosomes result from the
abnormal fusion of two chromosome pieces, each of which includes a centromere.
These structures are unstable and often involve a loss of some genetic material.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 57

 FIGURE 3.19: A dicentric chromosome results from the abnormal
fusion of pieces of two chromosomes, creating a chromosome with
two centromeres.

Ring chromosomes
Ring chromosomes (Figure 3.20) usually occur when a chromosome breaks in two
places, typically at the ends of the p and q arms, and then the arms fuse together to
form a circular structure. The ring may or may not include the centromere, depending on
where on the chromosome the breaks occur. In many cases, genetic material near the
ends of the chromosome is lost.

FIGURE 3.20: A ring chromosome occurs when the two ends of a

chromosome break and then fuse together, creating a ring shape.

Many cancer cells also have changes in their chromosome structure. These changes
are not inherited; they occur in somatic cells (cells other than eggs or sperm) during the
formation or progression of a cancerous tumor.

For more information about structural changes to chromosomes:

The National Human Genome Research Institute provides a list of questions and
answers about chromosome abnormalities (https://www.genome.gov/about-genomics/fa
ct-sheets/Chromosome-Abnormalities-Fact-Sheet), including a glossary of related terms.

Chromosome Disorder Outreach offers a fact sheet on this topic titled Introduction to
Chromosomes (https://chromodisorder.org/introduction-to-chromosomes/). This
resource includes illustrated explanations of several chromosome abnormalities.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 58

The Centre for Genetics Education provides a fact sheet about chromosome changes (h
ttps://www.genetics.edu.au/SitePages/Chromosome-changes.aspx).

The University of Leicester's Virtual Genetics Education Center provides an explanation

of structural chromosome aberrations (https://www2.le.ac.uk/projects/vgec/healthprof/to
pics/patterns-of-inheritance/chromosomal-abnormalities#structural-aberrations).

Your Genome from the Wellcome Genome Campus discusses chromosome disorders (
https://www.yourgenome.org/facts/what-is-a-chromosome-disorder), including types of
structural abnormalities in chromosomes that are involved in genetic diseases.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 59

 3.8 Can changes in noncoding DNA affect health and
development?
It is well established that changes in genes can alter a protein’s function in the body,
potentially causing health problems. Scientists have determined that changes in regions
of DNA that do not contain genes (noncoding DNA) can also lead to disease.

Many regions of noncoding DNA play a role in the control of gene activity, meaning they
help determine when and where certain genes are turned on or off. Other regions of
noncoding DNA are important for protein assembly. By altering one of these regions, a
variant (also known as a mutation) in noncoding DNA can turn on a gene and cause a
protein to be produced in the wrong place or at the wrong time. Alternatively, a variant
can reduce or eliminate the production of an important protein when it is needed. Not all
changes in noncoding DNA have an impact on health, but those that alter the pattern of
a critical protein can disrupt normal development or cause a health problem.

Variants in noncoding DNA have been linked to several types of cancer and
developmental disorders such as isolated Pierre Robin sequence. This condition is
caused by changes in regions of noncoding DNA that act as enhancer elements.
Enhancers attach proteins that help turn on particular genes. The enhancers altered in
isolated Pierre-Robin sequence control the activity of the SOX9 gene.

In addition to enhancer elements, variants in noncoding DNA can disrupt other

regulatory elements. These other elements include promoters, where proteins that turn
on genes attach; insulators, where proteins that help shape the activity of genes in
different ways attach; and silencers, where proteins that turn off genes attach.

Some regions of noncoding DNA provide instructions for making certain kinds of RNA
molecules that play roles in regulating gene activity or assembling proteins. Variants
that interrupt these functional RNA molecules, such as transfer RNAs, microRNAs, or
long noncoding RNAs, have also been implicated in disease.

The same types of genetic changes that occur in genes or that alter the structure of
chromosomes can affect health and development when they occur in noncoding DNA.
These alterations include changes in single DNA building blocks (substitution variants),
insertions, deletions, duplications, and translocations. Noncoding DNA variants can be
inherited from a parent or acquired during a person’s life.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 60

Much is still unknown about how to identify regions of noncoding DNA that have a
function in cells and the roles such regions play. As a result, linking genetic changes in
noncoding DNA to their effects on certain genes and to health conditions is difficult. The
roles of noncoding DNA and the effects that genetic changes in noncoding DNA have
on the body are growing areas of research.

Scientific journal articles for further reading

Scacheri CA, Scacheri PC. Mutations in the noncoding genome. Curr Opin Pediatr.
2015 Dec;27(6):659-64. doi: 10.1097/MOP.0000000000000283. Review. PubMed:
26382709; Free full text from PubMed Central: PMC5084913.

Chatterjee S, Ahituv N. Gene Regulatory Elements, Major Drivers of Human Disease.

Annu Rev Genomics Hum Genet. 2017 Aug 31;18:45-63. doi: 10.1146/annurev-genom-
091416-035537. Epub 2017 Apr 7. Review. PubMed: 28399667.

Gordon CT, Attanasio C, Bhatia S, Benko S, Ansari M, Tan TY, Munnich A, Pennacchio
LA, Abadie V, Temple IK, Goldenberg A, van Heyningen V, Amiel J, FitzPatrick D,
Kleinjan DA, Visel A, Lyonnet S. Identification of novel craniofacial regulatory domains
located far upstream of SOX9 and disrupted in Pierre Robin sequence. Hum Mutat.
2014 Aug;35(8):1011-20. doi: 10.1002/humu.22606. PubMed: 24934569; Free full text
from PubMed Central: PMC4389788.

Read more about the role of noncoding DNA in health and disease:
University of California, San Francisco: The Mysterious 98%: Scientists Look to Shine
Light on Our Dark Genome (https://www.ucsf.edu/news/2017/02/405686/mysterious-98-
scientists-look-shine-light-our-dark-genome)

Duke University: Variation in “Junk” DNA Leads to Trouble (https://today.duke.edu/2016

/08/variation-%E2%80%9Cjunk%E2%80%9D-dna-leads-trouble)

HEDD: Human Enhancer Disease Database (https://zdzlab.einsteinmed.edu/1/hedd.ph

p)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 61

 3.9 Can changes in mitochondrial DNA affect health and
development?
Mitochondria (Figure 1.5) are structures within cells that convert the energy from food
into a form that cells can use. Although most DNA is packaged in chromosomes within
the nucleus, mitochondria also have a small amount of their own DNA (known as
mitochondrial DNA or mtDNA). In some cases, inherited changes in mitochondrial DNA
can cause problems with growth, development, and function of the body’s systems.
These variants (also known as mutations) disrupt the mitochondria’s ability to generate
energy efficiently for cells.

Conditions caused by variants in mitochondrial DNA often involve multiple organ

systems. The effects of these conditions are most pronounced in organs and tissues
that require a lot of energy (such as the heart, brain, and muscles). Although the health
consequences of inherited mitochondrial DNA alterations vary widely, frequently
observed features include muscle weakness and wasting, problems with movement,
diabetes, kidney failure, heart disease, loss of intellectual functions (dementia), hearing
loss, and problems involving the eyes and vision.

Genetic changes that are not inherited (which are known as somatic variants) may also
occur in mitochondrial DNA. Somatic variants occur in the DNA of certain cells (not
sperm or egg cells) during a person’s lifetime and are not passed to future generations.
Because mitochondrial DNA has a limited ability to repair errors, these variants tend to
build up over time. A buildup of somatic variants in mitochondrial DNA has been
associated with some forms of cancer and an increased risk of certain age-related
disorders such as heart disease, Alzheimer's disease, and Parkinson's disease.
Additionally, research suggests that the progressive accumulation of these variants over
a person’s lifetime may play a role in the normal process of aging.

For more information about conditions caused by mitochondrial DNA

changes:
An overview of mitochondrial disorders (https://www.ncbi.nlm.nih.gov/books/NBK1224/)
is available from GeneReviews.

The Muscular Dystrophy Association offers an introduction to mitochondrial disorders as

part of their fact sheet called Mitochondrial Myopathies (https://www.mda.org/disease/mi
tochondrial-myopathies).

The Neuromuscular Disease Center at Washington University in St. Louis provides an

in-depth description of many mitochondrial disorders (https://neuromuscular.wustl.edu/
mitosyn.html).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 62

 3.10 What are complex or multifactorial disorders?
Researchers are learning that nearly all conditions and diseases have a genetic
component. Some disorders, such as sickle cell disease and cystic fibrosis, are caused
by variants (also known as mutations) in single genes. The causes of many other
disorders, however, are much more complex. Common health problems such as heart
disease, type 2 diabetes, and obesity do not have a single genetic cause—they are
influenced by multiple genes (polygenic) in combination with lifestyle and environmental
factors, such as exercise, diet, or pollutant exposures. Conditions caused by many
contributing factors are called complex or multifactorial disorders.

Although complex disorders often cluster in families, they do not have a clear-cut
pattern of inheritance. It may be difficult to identify the role of genetics in these disorders,
particularly because families often also share environments and may have similar
lifestyles. This makes it difficult to determine a person’s risk of inheriting or passing on
these disorders. Complex disorders are also difficult to study and treat because the
specific factors that cause most of these disorders have not yet been identified.
Researchers continue to look for major contributing genes for many common, complex
disorders.

For more information about complex disorders:

MedlinePlus (https://medlineplus.gov/) provides additional information about specific
complex disorders such as diabetes and obesity and other reliable medical information

A fact sheet about the inheritance of multifactorial disorders (https://www.genetics.edu.a

u/SitePages/Environmental-and-Genetic-interactions.aspx) is available from the Centre
for Genetics Education.

The Children's Hospital of Wisconsin provides basic information about multifactorial

inheritance (https://childrenswi.org/medical-care/genetics-and-genomics-program/medic
al-genetics/multifactorial-inheritance) and examples of multifactorial disorders.

The National Human Genome Research Institute describes how researchers study
complex disorders (https://www.genome.gov/10000865/complex-disorders-background).

The Centers for Disease Control and Prevention provides a list of diseases and
conditions (https://www.cdc.gov/DiseasesConditions/) with additional information.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 63

 3.11 What does it mean to have a genetic predisposition to a
disease?
A genetic predisposition (sometimes also called genetic susceptibility) is an increased
likelihood of developing a particular disease based on a person's genetic makeup. A
genetic predisposition results from specific genetic variations that are often inherited
from a parent. These genetic changes contribute to the development of a disease but
do not directly cause it. Some people with a predisposing genetic variation will never get
the disease while others will, even within the same family.

Genetic variations can have large or small effects on the likelihood of developing a
particular disease. For example, certain variants (also called mutations) in the BRCA1
or BRCA2 genes greatly increase a person's risk of developing breast cancer and
ovarian cancer. Particular variations in other genes, such as BARD1 and BRIP1, also
increase breast cancer risk, but the contribution of these genetic changes to a person's
overall risk appears to be much smaller.

Current research is focused on identifying genetic changes that have a small effect on
disease risk but are common in the general population. Although each of these
variations only slightly increases a person's risk, having changes in several different
genes may combine to increase disease risk significantly. Changes in many genes,
each with a small effect, may underlie susceptibility to many common diseases,
including cancer, obesity, diabetes, heart disease, and mental illness. Researchers are
working to calculate an individual’s estimated risk for developing a common disease
based on the combination of variants in many genes across their genome. This
measure, known as the polygenic risk score, is expected to help guide healthcare
decisions in the future.

In people with a genetic predisposition, the risk of disease can depend on multiple
factors in addition to an identified genetic change. These include other genetic factors
(sometimes called modifiers) as well as lifestyle and environmental factors. Diseases
that are caused by a combination of factors are described as multifactorial. Although a
person's genetic makeup cannot be altered, some lifestyle and environmental
modifications (such as having more frequent disease screenings and maintaining a
healthy weight) may be able to reduce disease risk in people with a genetic
predisposition.

For more information about genetic predisposition to disease:

The Genetic Science Learning Center at the University of Utah provides more
information about calculating the risk of genetic diseases and predicting disease based
on family history (https://learn.genetics.utah.edu/content/history/geneticrisk/).

More detailed information about the genetics of breast and ovarian cancer (https://www.
cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq), as well as other cancers (http
s://www.cancer.gov/publications/pdq/information-summaries/genetics), is available from
the National Cancer Institute.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 64

The National Human Genome Research Institute explains the calculation of polygenic
risk scores (https://www.genome.gov/Health/Genomics-and-Medicine/Polygenic-risk-sc
ores) and what information the scores can provide.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 65

 3.12 How are gene variants involved in evolution?
Evolution is the process by which populations of organisms change over generations.
Genetic variations underlie these changes. Genetic variations can arise from gene
variants (also called mutations) or from a normal process in which genetic material is
rearranged as a cell is getting ready to divide (known as genetic recombination).
Genetic variations that alter gene activity or protein function can introduce different traits
in an organism. If a trait is advantageous and helps the individual survive and reproduce,
the genetic variation is more likely to be passed to the next generation (a process
known as natural selection). Over time, as generations of individuals with the trait
continue to reproduce, the advantageous trait becomes increasingly common in a
population, making the population different than an ancestral one. Sometimes the
population becomes so different that it is considered a new species.

Not all variants influence evolution. Only hereditary variants, which occur in egg or
sperm cells, can be passed to future generations and potentially contribute to evolution.
Some variants occur during a person’s lifetime in only some of the body’s cells and are
not hereditary, so natural selection cannot play a role. Also, many genetic changes have
no impact on the function of a gene or protein and are not helpful or harmful. In addition,
the environment in which a population of organisms lives is integral to the selection of
traits. Some differences introduced by variants may help an organism survive in one
setting but not in another—for example, resistance to a certain bacteria is only
advantageous if that bacteria is found in a particular location and harms those who live
there.

So why do some harmful traits, like genetic diseases, persist in populations instead of
being removed by natural selection? There are several possible explanations, but in
many cases, the answer is not clear. For some conditions, such as the neurological
condition Huntington disease, signs and symptoms occur later in life, typically after a
person has children, so the gene variant can be passed on despite being harmful. For
other harmful traits, a phenomenon called reduced penetrance, in which some
individuals with a disease-associated variant do not show signs and symptoms of the
condition, can also allow harmful genetic variations to be passed to future generations.
For some conditions, having one altered copy of a gene in each cell is advantageous,
while having two altered copies causes disease. The best-studied example of this
phenomenon is sickle cell disease: Having two altered copies of the HBB gene in each
cell results in the disease, but having only one copy provides some resistance to
malaria. This disease resistance helps explain why the variants that cause sickle cell
disease are still found in many populations, especially in areas where malaria is
prevalent.

To find out more about the role of gene variants in evolution:

National Institute of General Medical Sciences: The New Genetics Chapter 3: Life’s
Genetic Tree (https://www.nigms.nih.gov/education/Booklets/the-new-genetics/Pages/H
ome.aspx)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 66

Learn.Genetics from the University of Utah: Evolution: DNA and the Unity of Life (https:/
/learn.genetics.utah.edu/content/evolution/)

Cold Spring Harbor Lab: Genetic Origins (http://www.geneticorigins.org/)

Understanding Evolution from the University of California Museum of Paleontology:

Huntington’s Chorea: Evolution and Genetic Disease (https://evolution.berkeley.edu/evo
library/article/0_0_0/medicine_05)

Understanding Evolution from the University of California Museum of Paleontology:

Misconceptions About Natural Selection (https://evolution.berkeley.edu/evolibrary/article
/evo_32)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 67

 3.13 What information can statistics provide about a genetic
condition?
Statistical data can provide general information about how common a condition is, how
many people have the condition, or how likely it is that a person will develop the
condition. Statistics are not personalized, but they do offer estimates based on groups
of people. By taking into account a person's family history, medical history, and other
factors, a genetics professional can help interpret the statistics and explain what they
mean for an individual.

Some statistical terms are commonly used when describing genetic conditions and
other disorders. These terms include the following:

Incidence. The incidence of a gene variant (also called a gene mutation) or a genetic
disorder is the number of people in a specified group who develop a variant or disorder
during a particular time period. Incidence is often written in the form “1 in [a number]” or
as a total number of a population.
Example: About 1 in 200,000 people in the United States are diagnosed with
syndrome A each year. An estimated 15,000 people worldwide were diagnosed with
syndrome B last year.

Prevalence. The prevalence of a gene variant or a genetic disorder is the total number
of people in a specified group at a given time who are living with the variant or disorder.
This term includes both newly diagnosed and pre-existing cases in people of any age.
Prevalence is often written in the form “1 in [a number]” or as a total number of people
who have a condition.
Example: Approximately 1 in 100,000 people in the United States have syndrome A at
the present time. About 100,000 children worldwide currently have syndrome B.

Mortality. Mortality is the number of deaths from a particular disorder occurring in a

specified group per year. Mortality is usually expressed as a total number of deaths.
Example: An estimated 12,000 people worldwide died from syndrome C in 2020.

Lifetime risk. Lifetime risk is the average risk of developing a particular disorder at
some point during a lifetime. Lifetime risk is often written as a percentage or as “1 in [a
number].” It is important to remember that the risk per year or per decade is much lower
than the lifetime risk. In addition, other factors may increase or decrease a person's risk
as compared with the average.
Example: Approximately 1 percent of people in the United States develop disorder D
during their lifetimes. The lifetime risk of developing disorder D is 1 in 100.

For more information about understanding and interpreting statistics:

NIH News in Health offers an explanation of health statistics in their article "

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 68

Understanding Health Risks (https://newsinhealth.nih.gov/2016/10/understanding-health-risks)."

The New York Department of Health provides a basic explanation of statistical terms (ht
tps://www.health.ny.gov/diseases/chronic/basicstat.htm), including incidence,
prevalence, morbidity, and mortality.

More detailed information about health statistics is available from Woloshin, Schwartz,
and Welch's Know Your Chances: Understanding Health Statistics (https://www.ncbi.nl
m.nih.gov/books/NBK115435/), which is available through the NCBI Bookshelf.

The National Cancer Institute offers additional tools for understanding cancer statistics (
https://www.cancer.gov/about-cancer/understanding/statistics).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 69

 3.14 How are genetic conditions and genes named?

Naming genetic conditions

Genetic conditions are not named in one standard way (unlike genes, which are given
an official name and symbol by a formal committee). Doctors who treat families with a
new, previously unknown disorder are often the first to propose a name for the condition.
Later, healthcare professionals, researchers, people affected by the condition, and
other interested individuals may come together to revise the name to improve its
usefulness. Naming is important because it allows accurate and effective
communication about particular conditions, which will ultimately improve care and help
researchers find new approaches to treatment.

Condition names are often derived from one or a combination of sources:

• The basic genetic or biochemical defect that causes the condition (for example,
alpha-1 antitrypsin deficiency);
• The gene in which the variant (or mutation) that causes the condition occurs (for
example, TUBB4A-related leukodystrophy);
• One or more major signs or symptoms of the disorder (for example,
hypermanganesemia with dystonia, polycythemia vera, and cryptogenic cirrhosis);
• The parts of the body affected by the condition (for example, brain-lung-thyroid
syndrome);
• The name of a physician or researcher, often the first person to describe the
disorder (for example, Marfan syndrome, which was named after Dr. Antoine
Bernard-Jean Marfan);
• A geographic area (for example, familial Mediterranean fever, which occurs mainly
in populations bordering the Mediterranean Sea); or
• The name of a patient or family with the condition (for example, amyotrophic lateral
sclerosis is often called Lou Gehrig disease after the famous baseball player who
was diagnosed with the condition).

Conditions named after a specific person are called eponyms. They can be in the
possessive form (e.g., Alzheimer’s disease) or in the nonpossessive form (e.g., Down
syndrome).

Naming genes
The HUGO Gene Nomenclature Committee (HGNC) designates an official name and
symbol (an abbreviation of the name) for each known human gene. The HGNC is a
nonprofit organization funded by the U.S. National Human Genome Research Institute
and the UK's Wellcome Trust. The Committee has named more than 19,000 of the
estimated 20,000 to 25,000 protein-coding genes in the human genome.

During the research process, genes often acquire several alternate names and symbols

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 70

from researchers investigating the same gene. To resolve this confusion, the HGNC
assigns a unique name and symbol to each human gene, which allows effective
organization of genes in large databanks, aiding the advancement of research. For
specific information about how genes are named, refer to the HGNC's Guidelines for
Human Gene Nomenclature.

Learn more about the naming of conditions and genes:

Common sources for finding the names of genetic conditions include PubMed (https://p
ubmed.ncbi.nlm.nih.gov/) , GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK111
6/) , OMIM (https://omim.org/), GARD (https://rarediseases.info.nih.gov/) , MeSH (https:/
/meshb.nlm.nih.gov/) , and Orphanet (https://www.orpha.net/).

The official names and symbols of all human genes are found on the HUGO Gene
Nomenclature Committee (https://www.genenames.org/) (HGNC) website.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 71

 4
Inheriting Genetic Conditions
4.1 What does it mean if a disorder seems to run in my
family?
A particular disorder might be described as “running in a family” if more than one person
in the family has the condition. Some disorders that affect multiple family members are
caused by gene variants (also known as mutations), which can be inherited (passed
down from parent to child). Other conditions that appear to run in families are not
caused by variants in single genes. Instead, environmental factors such as dietary
habits, pollutants, or a combination of genetic and environmental factors are responsible
for these disorders.

It is not always easy to determine whether a condition in a family is inherited. A genetics

professional can use a person’s family health history (a record of health information
about a person’s immediate and extended family) to help determine whether a disorder
has a genetic component. He or she will ask about the health of people from several
generations of the family, usually first-, second-, and third-degree relatives.

First-degree relatives. Parents, children, brothers, and sisters

Second-degree relatives. Grandparents, aunts and uncles, nieces and nephews, and
grandchildren

Third-degree relatives. First cousins

This condition affects members in each generation of a family. (Figure 4.1)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 72

 FIGURE 4.1: Three generations of a family with a genetic disorder.

For general information about disorders that run in families:

MedlinePlus Genetics provides consumer-friendly summaries of genetic conditions (http
s://medlineplus.gov/genetics/condition/). Each summary includes a brief description of
the condition, an explanation of its genetic cause, and information about the condition's
frequency and pattern of inheritance.

The Genetic Science Learning Center at the University of Utah offers interactive tools
about disorders that run in families (https://learn.genetics.utah.edu/content/history/).

The National Human Genome Research Institute offers a brief fact sheet called
Frequently Asked Questions About Genetic Disorders (https://www.genome.gov/For-Pat
ients-and-Families/Genetic-Disorders).

The Centre for Genetics Education provides an overview of genetic conditions (https://w
ww.genetics.edu.au/SitePages/Genetic-conditions.aspx).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 73

 4.2 Why is it important to know my family health history?
A family health history is a record of health information about a person and his or her
close relatives. A complete record includes information from three generations of
relatives, including children, brothers and sisters, parents, aunts and uncles, nieces and
nephews, grandparents, and cousins.

Families have similar genetic backgrounds, and often similar environments and
lifestyles. Together, these factors can give clues to conditions that may run in a family.
By noticing patterns of disorders among relatives, healthcare professionals can
determine whether an individual, family members, or future generations may be at an
increased risk of developing a particular condition.

A family health history can identify people with a higher-than-usual chance of having
common disorders, such as heart disease, high blood pressure, stroke, certain cancers,
and type 2 diabetes. These complex disorders are influenced by a combination of
genetic factors, environmental conditions, and lifestyle choices. A family history also can
provide information about the risk of rarer conditions caused by variants (mutations) in a
single gene, such as cystic fibrosis and sickle cell disease.

While a family health history provides information about the risk of specific health
concerns, having relatives with a condition does not mean that an individual will
definitely develop that condition. On the other hand, a person with no family history of a
disorder may still be at risk of developing the disorder.

Knowing one’s family health history allows a person to take steps to reduce his or her
risk. For people at an increased risk of certain cancers, healthcare professionals may
recommend more frequent screening (such as mammography or colonoscopy) starting
at an earlier age. Healthcare providers may also encourage regular checkups or testing
for people with a condition that runs in their family. Additionally, lifestyle changes such
as adopting a healthier diet, getting regular exercise, and quitting smoking help many
people lower their chances of developing heart disease and other common illnesses.

The easiest way to get information about family health history is to talk to relatives about
their health. Have they had any health problems, and when did they occur? A family
gathering could be a good time to discuss these issues. Additionally, obtaining medical
records and other documents (such as obituaries and death certificates) can help
complete a family health history. It is important to keep this information up-to-date and
to share it with a healthcare professional regularly.

For more information about family health history:

Additional educational resources related to information about family history (https://medl
ineplus.gov/familyhistory.html) is available from MedlinePlus.

The Centers for Disease Control and Prevention (CDC) provides information about the
importance of family health history (https://www.cdc.gov/genomics/famhistory/index.htm
). This resource also includes links to tools for recording family health information.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 74

The American Medical Association provides family history tools (https://www.ama-assn.
org/delivering-care/precision-medicine/collecting-family-history), including
questionnaires and forms for collecting medical information.

The National Institute on Aging provides suggestions on how to obtain a health history
form older individuals (https://www.nia.nih.gov/health/obtaining-older-patients-medical-hi
story).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 75

 4.3 What are the different ways a genetic condition can be
inherited?
Some genetic conditions are caused by variants (also known as mutations) in a single
gene. These conditions are usually inherited in one of several patterns, depending on
the gene involved:

Autosomal dominant. One altered copy of the gene in each cell is sufficient for a
person to be affected by an autosomal dominant disorder. In some cases, an affected
person inherits the condition from an affected parent (Figure 4.2). In others, the
condition may result from a new variant (Figure 4.3) in the gene and occur in people
with no history of the disorder in their family.
Example: Huntington disease, Marfan syndrome

Autosomal recessive. In autosomal recessive inheritance (Figure 4.4), variants occur

in both copies of the gene in each cell. The parents of an individual with an autosomal
recessive condition each carry one copy of the altered gene, but they typically do not
show signs and symptoms of the condition. Autosomal recessive disorders are typically
not seen in every generation of an affected family.
Example: cystic fibrosis, sickle cell disease

X-linked dominant. X-linked dominant (Figure 4.5) disorders are caused by variants in
genes on the X chromosome. In males (who have only one X chromosome), a variant in
the only copy of the gene in each cell causes the disorder. In females (who have two X
chromosomes), a variant in one of the two copies of the gene in each cell is sufficient to
cause the disorder. Females may experience less severe symptoms of the disorder
than males. A characteristic of X-linked inheritance is that fathers cannot pass X-linked
traits to their sons (no male-to-male transmission).
Example: fragile X syndrome

X-linked recessive. X-linked recessive (Figure 4.6) disorders are also caused by
variants in genes on the X chromosome. In males (who have only one X chromosome),
one altered copy of the gene in each cell is sufficient to cause the condition. In females
(who have two X chromosomes), a variant would have to occur in both copies of the
gene to cause the disorder. Because it is unlikely that females will have two altered
copies of this gene, males are affected by X-linked recessive disorders much more
frequently than females. A characteristic of X-linked inheritance is that fathers cannot
pass X-linked traits to their sons (no male-to-male transmission).
Example: hemophilia, Fabry disease

X-linked. Because the inheritance pattern of many X-linked disorders is not clearly
dominant or recessive, some experts suggest that conditions be considered X-linked
rather than X-linked dominant or X-linked recessive. X-linked disorders are caused by
variants in genes on the X chromosome, one of thetwo sex chromosomes in each cell.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 76

In males (who have only one X chromosome), an alteration in the only copy of the gene in
each cell is sufficient to cause the condition. In females (who have two X chromosomes),
one altered copy of the gene usually leads to less severe health problems than those in
affected males, or it may cause no signs or symptoms at all. A characteristic of X-linked
inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male
transmission).
Example: glucose-6-phosphate-dehydrogenase-deficiency, X-linked thrombocytopenia

Y-linked. A condition is considered Y-linked (Figure 4.7) if the altered gene that causes
the disorder is located on the Y chromosome, one of the two sex chromosomes in each
of a male's cells. Because only males have a Y chromosome, in Y-linked inheritance, a
variant can only be passed from father to son.
Example: Y chromosome infertility, some cases of Swyer syndrome

Codominant. In codominant inheritance (Figure 4.8), two different versions (alleles) of

a gene are expressed, and each version makes a slightly different protein. Both alleles
influence the genetic trait or determine the characteristics of the genetic condition.
Example: ABO blood group, alpha-1 antitrypsin deficiency

Mitochondrial. Mitochondrial inheritance (Figure 4.9), also known as maternal

inheritance, applies to genes in mitochondrial DNA. Mitochondria, which are structures
in each cell that convert molecules into energy, each contain a small amount of DNA.
Because only egg cells contribute mitochondria to the developing embryo, only females
can pass on mitochondrial variants to their children. Conditions resulting from variants in
mitochondrial DNA can appear in every generation of a family and can affect both males
and females, but fathers do not pass these disorders to their daughters or sons.
Example: Leber hereditary optic neuropathy (LHON)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 77

FIGURE 4.2: A parent with an autosomal dominant condition passes the
altered gene to two affected children. Two other children do not receive the
altered gene, and are unaffected.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 78

FIGURE 4.3: Neither parent has the mutated gene. A spontaneous
mutation occurs during the formation of an egg or sperm cell during
embryonic development, leading to an affected child.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 79

FIGURE 4.4: Both parents carry one copy of a mutated gene. In the next
generation, one child is affected with the condition, two children are carriers,
and one is unaffected and not a carrier.

FIGURE 4.5: Inheritance of an X-linked dominant disorder depends on

which parent is affected.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 80

FIGURE 4.6: Two generations of a family with an X-linked recessive
disorder. In this form of inheritance, the chance of being affected or being a
carrier depends on whether the mother or the father has the mutated gene
on the X chromosome.

FIGURE 4.7: A father and sons are affected with a Y-linked disorder, which

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 81

is caused by a genetic mutation on the Y chromosome. Females are
unaffected.

FIGURE 4.8: ABO blood type is an example of a trait with codominant

inheritance.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 82

 FIGURE 4.9: The inheritance of a mitochondrial disorder depends whether
the mother or the father has the mutation in mitochondrial DNA.

Many health conditions are caused by the combined effects of multiple genes
(described as polygenic) or by interactions between genes and the environment. Such
disorders usually do not follow the patterns of inheritance listed above. Examples of
conditions caused by variants in multiple genes or gene/environment interactions
include heart disease, type 2 diabetes, schizophrenia, and certain types of cancer. For
more information, please see What are complex or multifactorial disorders?

Disorders caused by changes in the number or structure of chromosomes also do not

follow the straightforward patterns of inheritance listed above. To read about how
chromosomal conditions occur, please see Are chromosomal disorders inherited?

Other genetic factors sometimes influence how a disorder is inherited. For an example,
please see What are genomic imprinting and uniparental disomy?

For more information about inheritance patterns:

The Centre for Genetics Education provides information about different inheritance
patterns:

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 83

• Autosomal dominant inheritance (https://www.genetics.edu.au/SitePages/Autosoma
l-dominant-inheritance.aspx)
• Autosomal recessive inheritance (https://www.genetics.edu.au/SitePages/Autosoma
l-recessive-inheritance.aspx)
• X-linked dominant inheritance (https://www.genetics.edu.au/SitePages/X-linked-do
minant-inheritance.aspx)
• X-linked recessive inheritance (https://www.genetics.edu.au/SitePages/X-linked-rec
essive-inheritance.aspx)
• Mitochondrial inheritance (https://www.genetics.edu.au/SitePages/Mitochondrial-Inh
eritance.aspx)

Additional information about inheritance patterns is available from The Merck Manual (ht
tps://www.merckmanuals.com/professional/special-subjects/general-principles-of-medic
al-genetics/single-gene-defects).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 84

 4.4 If a genetic disorder runs in my family, what are the
chances that my children will have the condition?
When a genetic disorder is diagnosed in a family, family members often want to know
the likelihood that they or their children will develop the condition. This can be difficult to
predict in some cases because many factors influence a person's chances of
developing a genetic condition. One important factor is how the condition is inherited.
For example:
• Autosomal dominant inheritance: A person affected by an autosomal dominant
disorder (Figure 4.2) has a 50 percent chance of passing the altered gene to each
child. The chance that a child will not inherit the altered gene is also 50 percent.
However, in some cases an autosomal dominant disorder results from a new (de
novo) variant (Figure 4.3) that occurs during the formation of egg or sperm cells or
early in embryonic development. In these cases, the child's parents are unaffected,
but the child may pass on the condition to his or her own children.
• Autosomal recessive inheritance: Two unaffected people who each carry one copy
of the altered gene for an autosomal recessive disorder (Figure 4.4) (carriers) have a
25 percent chance with each pregnancy of having a child affected by the disorder.
The chance with each pregnancy of having an unaffected child who is a carrier of
the disorder is 50 percent, and the chance that a child will not have the disorder and
will not be a carrier is 25 percent. If only one parent is a carrier of the altered gene
and the other parent does not carry the variant, none of their children will develop
the condition, and the chance with each pregnancy of having an unaffected child
who is a carrier is 50 percent.
• X-linked dominant inheritance: The chance of passing on an X-linked dominant
condition (Figure 4.5) differs between men and women because men have one X
chromosome and one Y chromosome, while women have two X chromosomes. A
man passes on his Y chromosome to all of his sons and his X chromosome to all of
his daughters. Therefore, the sons of a man with an X-linked dominant disorder will
not be affected, but all of his daughters will inherit the condition. A woman passes on
one or the other of her X chromosomes to each child. Therefore, a woman with an X-
linked dominant disorder has a 50 percent chance of having an affected daughter or
son with each pregnancy.
• X-linked recessive inheritance: Because of the difference in sex chromosomes, the
probability of passing on an X-linked recessive disorder (Figure 4.6) also differs
between men and women. The sons of a man with an X-linked recessive disorder
will not be affected, and his daughters will carry one copy of the altered gene. With
each pregnancy, a woman who carries an altered gene for X-linked recessive has a
50 percent chance of having sons who are affected and a 50 percent chance of
having daughters who carry one copy of the altered gene. Females with one gene
variant associated with an X-linked recessive disorder typically have no or very mild
signs or symptoms of the condition.
• X-linked: Because the inheritance pattern of many X-linked disorders is not clearly
dominant or recessive, some experts suggest that conditions be considered X-linked
rather than X-linked dominant or X-linked recessive.As above, the probability of

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 85

 passing on an X-linked disorder differs between men and women. The sons of a man with
an X-linked disorder will not be affected, but all of his daughters will inherit the
altered gene and may develop signs and symptoms of the condition. A woman
passes on one or the other of her X chromosomes to each child. Therefore, with
each pregnancy, a woman with an X-linked disorder has a 50 percent chance of
having a child with the altered gene. An affected daughter may have milder signs
and symptoms than an affected son.
• Y-linked inheritance: Because only males have a Y chromosome, only males can
be affected by and pass on Y-linked disorders (Figure 4.7). All sons of a man with a
Y-linked disorder will inherit the condition from their father.
• Codominant inheritance: In codominant inheritance (Figure 4.8), each parent
contributes a different version of a particular gene, and both versions influence the
resulting genetic trait. The chance of developing a genetic condition with codominant
inheritance, and the characteristic features of that condition, depend on which
versions of the gene are passed from parents to their child.
• Mitochondrial inheritance: Mitochondria, which are the energy-producing centers
inside cells, each contain a small amount of DNA. Disorders with mitochondrial
inheritance (Figure 4.9) result from variants in mitochondrial DNA. Although these
disorders can affect both males and females, only females can pass variants in
mitochondrial DNA to their children. A woman with a disorder caused by changes in
mitochondrial DNA will pass the variants to all of her daughters and sons, but the
children of a man with such a disorder will not inherit the variant.

It is important to note that the chance of passing on a genetic condition applies equally
to each pregnancy. For example, if a couple has a child with an autosomal recessive
disorder, the chance of having another child with the disorder is still 25 percent (or 1 in 4)
. Having one child with a disorder does not “protect” future children from inheriting the
condition. Conversely, having a child without the condition does not mean that future
children will definitely be affected.

Although the chances of inheriting a genetic condition appear straightforward, factors

such as a person's family history and the results of genetic testing can sometimes
modify those chances. In addition, some people with a disease-causing variant never
develop any health problems or may experience only mild symptoms of the disorder. If a
disease that runs in a family does not have a clear-cut inheritance pattern, predicting
the likelihood that a person will develop the condition can be particularly difficult.

Estimating the chance of developing or passing on a genetic disorder can be complex.

Genetics professionals can help people understand these chances and help them make
informed decisions about their health.

For more information about passing on a genetic disorder in a family:

MedlinePlus offers additional information about the chance of developing a genetic
disorder on the basis of its inheritance pattern:
• Autosomal dominant (https://medlineplus.gov/ency/article/002049.htm)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 86

• Autosomal recessive (https://medlineplus.gov/ency/article/002052.htm)
• X-linked dominant (https://medlineplus.gov/ency/article/002050.htm)
• X-linked recessive (https://medlineplus.gov/ency/article/002051.htm)

The Centre for Genetics Education provides an explanation of mitochondrial inheritance

(https://www.genetics.edu.au/SitePages/Mitochondrial-Inheritance.aspx).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 87

 4.5 What are reduced penetrance and variable expressivity?
Reduced penetrance and variable expressivity are factors that influence the effects of
particular genetic changes. These factors usually affect disorders that have an
autosomal dominant pattern of inheritance, although they are occasionally seen in
disorders with an autosomal recessive inheritance pattern.

Reduced penetrance
Penetrance refers to the proportion of people with a particular genetic variant (or gene
mutation) who exhibit signs and symptoms of a genetic disorder. If some people with
the variant do not develop features of the disorder, the condition is said to have reduced
(or incomplete) penetrance. Reduced penetrance often occurs with familial cancer
syndromes. For example, many people with a variant in the BRCA1 or BRCA2 gene
associated with an increased cancer risk will develop cancer during their lifetime, but
some people will not. Doctors cannot predict which people with these variants will
develop cancer or when the tumors will develop.

Reduced penetrance probably results from a combination of genetic, environmental,

and lifestyle factors, many of which are unknown. This phenomenon can make it
challenging for genetics professionals to interpret a person’s family medical history and
predict the risk of passing a genetic condition to future generations.

Variable expressivity
Although some genetic disorders exhibit little variation, most have signs and symptoms
that differ among affected individuals. Variable expressivity refers to the range of signs
and symptoms that can occur in different people with the same genetic condition. For
example, the features of Marfan syndrome vary widely— some people have only mild
symptoms (such as being tall and thin with long, slender fingers), while others also
experience life-threatening complications involving the heart and blood vessels.
Although the features are highly variable, most people with this disorder have a variant
in the same gene (FBN1).

As with reduced penetrance, variable expressivity is probably caused by a combination

of genetic, environmental, and lifestyle factors, most of which have not been identified. If
a genetic condition has highly variable signs and symptoms, it may be challenging to
diagnose.

For more information about reduced penetrance and variable

expressivity:
Additional information about penetrance and expressivity (https://www.merckmanuals.c
om/home/fundamentals/genetics/inheritance-of-single-gene-disorders) is available from
the Merck Manual Consumer Version.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 88

 4.6 What do geneticists mean by anticipation?
The signs and symptoms of some genetic conditions tend to become more severe and
appear at an earlier age as the disorder is passed from one generation to the next. This
phenomenon is called anticipation. Anticipation is most often seen with certain genetic
disorders of the nervous system, such as Huntington disease, myotonic dystrophy, and
fragile X syndrome.

Anticipation typically occurs with disorders that are caused by an unusual type of variant
(mutation) called a trinucleotide repeat expansion. A trinucleotide repeat is a sequence
of three DNA building blocks (nucleotides) that is repeated a number of times in a row.
DNA segments with an abnormal number of these repeats are unstable and prone to
errors during cell division. The number of repeats can change as the gene is passed
from parent to child. If the number of repeats increases, it is known as a trinucleotide
repeat expansion. In some cases, the trinucleotide repeat may expand until the gene
stops functioning normally. This expansion causes the features of some disorders to
become more severe with each successive generation.

Most genetic disorders have signs and symptoms that differ among affected individuals,
including affected people in the same family. Not all of these differences can be
explained by anticipation. A combination of genetic, environmental, and lifestyle factors
is probably responsible for the variability, although many of these factors have not been
identified. Researchers study multiple generations of affected family members and
consider the genetic cause of a disorder before determining that it shows anticipation.

For more information about anticipation:

The Merck Manual Professional Version provides a brief explanation of anticipation as
part of its chapter on nontraditional inheritance (https://www.merckmanuals.com/profess
ional/special-subjects/general-principles-of-medical-genetics/unusual-aspects-of-inherit
ance).

The Myotonic Dystrophy Foundation describes anticipation in the context of myotonic

dystrophy (https://www.myotonic.org/digital-academy/dm-anticipation-part-1).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 89

 4.7 What are genomic imprinting and uniparental disomy?
Genomic imprinting and uniparental disomy are factors that influence how some genetic
conditions are inherited.

Genomic imprinting
People inherit two copies of their genes—one from their mother and one from their
father. Usually both copies of each gene are active, or “turned on,” in cells. In some
cases, however, only one of the two copies is normally turned on. Which copy is active
depends on the parent of origin: some genes are normally active only when they are
inherited from a person’s father; others are active only when inherited from a person’s
mother. This phenomenon is known as genomic imprinting.

In genes that undergo genomic imprinting, the parent of origin is often marked, or “
stamped,” on the gene during the formation of egg and sperm cells. This stamping
process, called methylation, is a chemical reaction that attaches small molecules called
methyl groups to certain segments of DNA. These molecules identify which copy of a
gene was inherited from the mother and which was inherited from the father. The
addition and removal of methyl groups can be used to control the activity of genes.

Only a small percentage of all human genes undergo genomic imprinting. Researchers
are not yet certain why some genes are imprinted and others are not. They do know
that imprinted genes tend to cluster together in the same regions of chromosomes. Two
major clusters of imprinted genes have been identified in humans, one on the short (p)
arm of chromosome 11 (at position 11p15) and another on the long (q) arm of
chromosome 15 (in the region 15q11 to 15q13).

Uniparental disomy
Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome,
or part of a chromosome, from one parent and no copies from the other parent. UPD
can occur as a random event during the formation of egg or sperm cells or may happen
in early fetal development.

In many cases, UPD likely has no effect on health or development. Because most
genes are not imprinted, it doesn’t matter if a person inherits both copies from one
parent instead of one copy from each parent. In some cases, however, it does make a
difference whether a gene is inherited from a person’s mother or father. A person with
UPD may lack any active copies of essential genes that undergo genomic imprinting.
This loss of gene function can lead to delayed development, intellectual disability, or
other health problems.

Several genetic disorders can result from UPD or a disruption of normal genomic
imprinting. The most well-known conditions include Prader-Willi syndrome, which is
characterized by uncontrolled eating and obesity, and Angelman syndrome, which
causes intellectual disability and impaired speech. Both of these disorders can be

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 90

caused by UPD or other errors in imprinting involving genes on the long arm of chromosome 15.
Other conditions, such as Beckwith-Wiedemann syndrome (a disorder characterized by
accelerated growth and an increased risk of cancerous tumors), are associated with
abnormalities of imprinted genes on the short arm of chromosome 11.

For more information about genomic imprinting and UPD:

The National Human Genome Research Institute provides a definition of genetic
imprinting (https://www.genome.gov/genetics-glossary/Genetic-Imprinting) in its Talking
Glossary of Genetic Terms.

The University of Utah offers a basic overview of genomic imprinting (https://learn.geneti

cs.utah.edu/content/epigenetics/imprinting/).

Additional information about epigenetics, including genomic imprinting (https://www.gen

etics.edu.au/SitePages/Epigenetics.aspx) is available from the Centre for Genetics
Education.

Geneimprint, a website about genomic imprinting, provides an introduction to imprinting

(http://www.geneimprint.com/site/what-is-imprinting) as well as related articles and a list
of imprinted genes (http://www.geneimprint.com/site/genes-by-species).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 91

 4.8 Are chromosomal disorders inherited?
Although it is possible to inherit some types of chromosomal abnormalities, most
chromosomal disorders (such as Down syndrome and Turner syndrome) are not
passed from one generation to the next.

Some chromosomal conditions are caused by changes in the number of chromosomes.

These changes are not inherited, but occur as random events during the formation of
reproductive cells (eggs and sperm). An error in cell division called nondisjunction
results in reproductive cells with an abnormal number of chromosomes. For example, a
reproductive cell may accidentally gain or lose one copy of a chromosome. If one of
these atypical reproductive cells contributes to the genetic makeup of a child, the child
will have an extra or missing chromosome in each of the body’s cells.

Changes in chromosome structure can also cause chromosomal disorders. Some

changes in chromosome structure can be inherited, while others occur as random
accidents during the formation of reproductive cells or in early fetal development.
Because the inheritance of these changes can be complex, people concerned about
this type of chromosomal abnormality may want to talk with a genetics professional.

Some cancer cells also have changes in the number or structure of their chromosomes.
Because these changes occur in somatic cells (cells other than eggs and sperm), they
cannot be passed from one generation to the next.

For more information about how chromosomal changes occur:

As part of its fact sheet on chromosome abnormalities, the National Human Genome
Research Institute provides a discussion of how chromosome abnormalities happen. (ht
tps://www.genome.gov/about-genomics/fact-sheets/Chromosome-Abnormalities-Fact-S
heet)

The Chromosome Disorder Outreach fact sheet Introduction to Chromosomes (https://c

hromodisorder.org/introduction-to-chromosomes/) explains how structural changes
occur.

Additional information about how chromosomal changes happen (https://www.urmc.roch

ester.edu/encyclopedia/content.aspx?ContentTypeID=90&ContentID=P02126) is
available from the University of Rochester Medical Center.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 92

 4.9 Why are some genetic conditions more common in
particular ethnic groups?
Some genetic disorders are more likely to occur among people who trace their ancestry
to a particular geographic area. People in an ethnic group often share certain versions
of their genes, which have been passed down from common ancestors. If one of these
shared genes contains a disease-causing variant (also known as a mutation), a
particular genetic disorder may be more frequently seen in the group.

Examples of genetic conditions that are more common in particular ethnic groups are
sickle cell disease, which is more common in people of African, African American, or
Mediterranean heritage; and Tay-Sachs disease, which is more likely to occur among
people of Ashkenazi (eastern and central European) Jewish or French Canadian
ancestry. It is important to note, however, that these disorders can occur in any ethnic
group.

For more information about genetic disorders that are more common
in certain groups:
The Norton & Elaine Sarnoff Center for Jewish Genetics provides information on
disorders that occur more frequently in people with Jewish ancestry, including genetic
traits that tend to be more common in Ashkenazi Jews (https://www.juf.org/cjg/Ashkena
zi-Jewish-Disorders.aspx) and Sephardic Jews (https://www.juf.org/cjg/Sephardic-Jewis
h-Disorders.aspx).

The Centers of Disease Control and Prevention provides data on the prevalence of
sickle cell disease (https://www.cdc.gov/ncbddd/sicklecell/data.html) in various
populations in the United States.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 93

 4.10 What is heritability?
Heritability is a measure of how well differences in people’s genes account for
differences in their traits. Traits can include characteristics such as height, eye color,
and intelligence, as well as disorders like schizophrenia and autism spectrum disorder.
In scientific terms, heritability is a statistical concept (represented as h²) that describes
how much of the variation in a given trait can be attributed to genetic variation. An
estimate of the heritability of a trait is specific to one population in one environment, and
it can change over time as circumstances change.

Heritability estimates range from zero to one. A heritability close to zero indicates that
almost all of the variability in a trait among people is due to environmental factors, with
very little influence from genetic differences. Characteristics such as religion or
language spoken have a heritability of zero because they are not under genetic control.
A heritability close to one indicates that almost all of the variability in a trait comes from
genetic differences, with very little contribution from environmental factors. Many
disorders that are caused by variants (also known as mutations) in single genes, such
as phenylketonuria (PKU), have high heritability. Most complex traits in people, such as
intelligence and multifactorial diseases, have a heritability somewhere in the middle,
suggesting that their variability is due to a combination of genetic and environmental
factors.

Heritability has historically been estimated from studies of twins. Identical twins have
almost no differences in their DNA, while fraternal twins share, on average, 50 percent
of their DNA. If a trait appears to be more similar in identical twins than in fraternal twins
(when they were raised together in the same environment), genetic factors likely play an
important role in determining that trait. By comparing a trait in identical twins versus
fraternal twins, researchers can calculate an estimate of its heritability.

Heritability can be difficult to understand, so there are many misconceptions about what
it can and cannot tell us about a given trait:
• Heritability does not indicate what proportion of a trait is determined by genes and
what proportion is determined by environment. So, a heritability of 0.7 does not
mean that a trait is 70% caused by genetic factors; it means that 70% of the
variability in the trait in a population is due to genetic differences among people.
• Knowing the heritability of a trait does not provide information about which genes or
environmental influences are involved, or how important they are in determining the
trait.
• Heritable is not the same as familial. A trait is described as familial if it is shared by
members of a family. Traits can appear in families for many reasons in addition to
genetics, such as similarities in lifestyle and environment. For example, the
language that is spoken tends to be shared in families, but it has no genetic
contribution and so is not heritable.
• Heritability does not give any information about how easy or difficult it is to change a
trait. For example, hair color is a trait with high heritability, but it is very easy to
change with dye.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 94

If heritability provides such limited information, why do researchers study it? Heritability
is of particular interest in understanding traits that are very complex with many
contributing factors. Heritability can give initial clues as to the relative influences of “
nature” (genetics) and “nurture” (environment) on complex traits, and it can give
researchers a place to start teasing apart the factors that influence these traits.

Scientific articles for further reading

Moore DS, Shenk D. The heritability fallacy. Wiley Interdiscip Rev Cogn Sci. 2017 Jan;
8(1-2). doi: 10.1002/wcs.1400. Epub 2016 Dec 1. Review. PubMed: 27906501.

Tenesa A, Haley CS. The heritability of human disease: estimation, uses and abuses.
Nat Rev Genet. 2013 Feb;14(2):139-49. doi: 10.1038/nrg3377. Review. PubMed:
23329114.

For more information about heritability:

Indiana University Bloomington: Heritability: What It Means and Why It’s Important (http
s://blogs.iu.edu/sciu/2017/04/11/heritability/)

Stanford Encyclopedia of Philosophy: Heritability (https://plato.stanford.edu/entries/here

dity/)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 95

 5
Genetics and Human Traits
5.1 Are fingerprints determined by genetics?
Each person’s fingerprints are unique, which is why they have long been used as a way
to identify individuals. Surprisingly little is known about the factors that influence a
person’s fingerprint patterns. Like many other complex traits, studies suggest that both
genetic and environmental factors play a role.

A person’s fingerprints are based on the patterns of skin ridges (called dermatoglyphs)
on the pads of the fingers. These ridges are also present on the toes, the palms of the
hands, and the soles of the feet. Although the basic whorl, arch, and loop patterns may
be similar, the details of the patterns are specific to each individual.

Dermatoglyphs develop before birth and remain the same throughout life. The ridges
begin to develop during the third month of fetal development, and they are fully formed
by the sixth month. The function of these ridges is not entirely clear, but they likely
increase sensitivity to touch.

The basic size, shape, and spacing of dermatoglyphs appear to be influenced by

genetic factors. Studies suggest that multiple genes are involved, so the inheritance
pattern is not straightforward. Genes that control the development of the various layers
of skin, as well as the muscles, fat, and blood vessels underneath the skin, may all play
a role in determining the pattern of ridges. The finer details of the patterns of skin ridges
are influenced by other factors during fetal development, including substances taken
during pregnancy and the environment inside the womb. These developmental factors
cause each person’s dermatoglyphs to be different from everyone else’s. Even identical
twins, who have the same DNA, have different fingerprints.

Few genes involved in dermatoglyph formation have been identified. Rare diseases
characterized by abnormal or absent dermatoglyphs provide some clues as to their
genetic basis. For example, a condition known as adermatoglyphia is characterized by
an absence of dermatoglyphs, sometimes with other abnormalities of the skin.
Adermatoglyphia is caused by mutations in a gene called SMARCAD1. Although this
gene is clearly important for the formation of dermatoglyphs, its role in their
development is unclear.

Scientific journal articles for further reading

Burger B, Fuchs D, Sprecher E, Itin P. The immigration delay disease: adermatoglyphia-
inherited absence of epidermal ridges. J Am Acad Dermatol. 2011 May;64(5):974-80.
doi: 10.1016/j.jaad.2009.11.013. Epub 2010 Jul 8.PubMed: 20619487.

Nousbeck J, Burger B, Fuchs-Telem D, Pavlovsky M, Fenig S, Sarig O, Itin P, Sprecher

E. A mutation in a skin-specific isoform of SMARCAD1 causes autosomal-dominant
adermatoglyphia. Am J Hum Genet. 2011 Aug 12;89(2):302-7. doi: 10.1016/j.ajhg.2011.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 96

07.004. Epub 2011 Aug 4. PubMed: 21820097. Free full-text available from PubMed
Central: PMC3155166.

Warman PH, Ennos A.R. Fingerprints are unlikely to increase the friction of primate
fingerpads. J Exp Biol. 2009 Jul;212(Pt 13):2016-22. doi: 10.1242/jeb.028977. PubMed:
19525427.

Sudha PI, Singh J, Sodhi GS. The Dermal Ridges as the Infallible Signature of Skin: An
Overview. Indian J Dermatol. 2021 Nov-Dec;66(6):649-653. doi: 10.4103/ijd.ijd_1123_
20. PubMed: 35283510. Free full-text available from PubMed Central: PMC8906331.

To find out more about the influence of genetics on the formation of

fingerprints:
The Washington State Twin Registry has an FAQ about the fingerprints of identical
twins (https://wstwinregistry.org/2015/10/01/do-identical-twins-have-identical-fingerprints
/).

OMIM.org provides more detailed genetic information about dermatoglyphs (http://omim

.org/entry/125590) and adermatoglyphia (http://omim.org/entry/136000).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 97

 5.2 Is eye color determined by genetics?
A person’s eye color results from pigmentation of a structure called the iris, which
surrounds the small black hole in the center of the eye (the pupil) and helps control how
much light can enter the eye. The color of the iris ranges on a continuum from very light
blue to dark brown. Most of the time eye color is categorized as blue, green/hazel, or
brown. Brown is the most frequent eye color worldwide.

Eye color is determined by variations in a person’s genes. Most of the genes associated
with eye color are involved in the production, transport, or storage of a pigment called
melanin. Eye color is directly related to the amount of melanin in the front layers of the
iris. People with brown eyes have a large amount of melanin in the iris, while people
with blue eyes have much less of this pigment.

A particular region on chromosome 15 plays a major role in eye color. Within this region,
there are two genes located very close together: OCA2 and HERC2. The protein
produced from the OCA2 gene, known as the P protein, is involved in the maturation of
melanosomes, which are cellular structures that produce and store melanin. The P
protein therefore plays a crucial role in the amount and quality of melanin that is present
in the iris. Several common variations (polymorphisms) in the OCA2 gene reduce the
amount of functional P protein that is produced. Less P protein means that less melanin
is present in the iris, leading to blue eyes instead of brown in people with a
polymorphism in this gene.

A region of the nearby HERC2 gene known as intron 86 contains a segment of DNA
that controls the activity (expression) of the OCA2 gene, turning it on or off as needed.
At least one polymorphism in this area of the HERC2 gene has been shown to reduce
the expression of OCA2 and decrease P protein production, leading to less melanin in
the iris and lighter-colored eyes.

Several other genes play smaller roles in determining eye color. Some of these genes
are also involved in skin and hair coloring. Genes with reported roles in eye color
include ASIP, IRF4, SLC24A4, SLC24A5, SLC45A2, TPCN2, TYR, and TYRP1. The
effects of these genes likely combine with those of OCA2 and HERC2 to produce a
continuum of eye colors in different people.

Researchers used to think that eye color was determined by a single gene and followed
a simple inheritance pattern in which brown eyes were dominant to blue eyes. Under
this model, it was believed that parents who both had blue eyes could not have a child
with brown eyes. However, later studies showed that this model was too simplistic.
Although it is uncommon, parents with blue eyes can have children with brown eyes.
The inheritance of eye color is more complex than originally suspected because multiple
genes are involved. While a child’s eye color can often be predicted by the eye colors of
his or her parents and other relatives, genetic variations sometimes produce
unexpected results.

Several disorders that affect eye color have been described. Ocular albinism is
characterized by severely reduced pigmentation of the iris, which causes very light-

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 98

colored eyes and significant problems with vision. Another condition called oculocutaneous
albinism affects the pigmentation of the skin and hair in addition to the eyes. Affected
individuals tend to have very light-colored irises, fair skin, and white or light-colored hair.
Both ocular albinism and oculocutaneous albinism result from mutations in genes
involved in the production and storage of melanin. Another condition called
heterochromia is characterized by different-colored eyes in the same individual.
Heterochromia can be caused by genetic changes or by a problem during eye
development, or it can be acquired as a result of a disease or injury to the eye.

Eye anatomy (Figure 5.1)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 99

 FIGURE 5.1: Two-panel drawing shows the outside and inside of the eye.
The top panel shows outside of the eye including the eyelid, pupil, sclera,
and iris; the bottom panel shows inside of the eye including the cornea,
lens, ciliary body, retina, choroid, optic nerve, and vitreous humor.

To learn more about the genetics of eye color:

The Tech Museum of Innovation at Stanford University provides a Q&A explaining
how brown-eyed parents can have blue-eyed children (https://genetics.thetech.org/ask-
a-geneticist/brown-eyed-parents-blue-eyed-kids).

More detailed information about ocular albinism (http://omim.org/entry/300500) and

oculocutaneous albinism (http://omim.org/entry/203100), as well as the genetics of eye,

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 100

hair, and skin color variation (http://omim.org/entry/227220), is available from OMIM.org.

Additional information from MedlinePlus provides a brief description of heterochromia (h

ttps://medlineplus.gov/ency/article/003319.htm). Further information about this condition
is provided by the American Academy of Ophthalmology (https://www.aao.org/eye-healt
h/diseases/what-is-heterochromia).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 101

 5.3 Is intelligence determined by genetics?
Like most aspects of human behavior and cognition, intelligence is a complex trait that
is influenced by both genetic and environmental factors.

Intelligence is challenging to study, in part because it can be defined and measured in

different ways. Most definitions of intelligence include the ability to learn from
experiences and adapt to changing environments. Elements of intelligence include the
ability to reason, plan, solve problems, think abstractly, and understand complex ideas.
Many studies rely on a measure of intelligence called the intelligence quotient (IQ).

Researchers have conducted many studies to look for genes that influence intelligence.
Many of these studies have focused on similarities and differences in IQ within families,
particularly looking at adopted children and twins. Other studies have examined
variations across the entire genomes of many people (an approach called genome-wide
association studies or GWAS) to determine whether any specific areas of the genome
are associated with IQ. Studies have not conclusively identified any genes that have
major roles in differences in intelligence. It is likely that a large number of genes are
involved, each of which makes only a small contribution to a person’s intelligence. Other
areas that contribute to intelligence, such as memory and verbal ability, involve
additional genetic factors.

Intelligence is also strongly influenced by the environment. During a child's development,

factors that contribute to intelligence include their home environment and parenting,
education and availability of learning resources, and healthcare and nutrition. A person’
s environment and genes influence each other, and it can be challenging to tease apart
the effects of the environment from those of genetics. For example, if a person's level of
intelligence is similar to that of their parents, is that similarity due to genetic factors
passed down from parent to child, to shared environmental factors, or (most likely) to a
combination of both? It is clear that both environmental and genetic factors play a part
in determining intelligence.

Scientific journal articles for further reading

Plomin R, Deary IJ. Genetics and intelligence differences: five special findings. Mol
Psychiatry. 2015 Feb;20(1):98-108. doi: 10.1038/mp.2014.105. Epub 2014 Sep 16.
Review. PubMed: 25224258. Free full-text available from PubMed Central:
PMC4270739.

Plomin R, von Stumm S. The new genetics of intelligence. Nat Rev Genet. 2018 Mar;
19(3):148-159. doi: 10.1038/nrg.2017.104. Epub 2018 Jan 8. PubMed: 29335645. Free
full-text available from PubMed Central: PMC5985927.

Sniekers S, Stringer S, Watanabe K, Jansen PR, Coleman JRI, Krapohl E, Taskesen E,

Hammerschlag AR, Okbay A, Zabaneh D, Amin N, Breen G, Cesarini D, Chabris CF,
Iacono WG, Ikram MA, Johannesson M, Koellinger P, Lee JJ, Magnusson PKE, McGue
M, Miller MB, Ollier WER, Payton A, Pendleton N, Plomin R, Rietveld CA, Tiemeier H,
van Duijn CM, Posthuma D. Genome-wide association meta-analysis of 78,308

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 102

individuals identifies new loci and genes influencing human intelligence. Nat Genet. 2017 Jul;
49(7):1107-1112. doi: 10.1038/ng.3869. Epub 2017 May 22. Erratum in: Nat Genet.
2017 Sep 27;49(10 ):1558. PubMed: 28530673. Free full-text available from PubMed
Central: PMC5665562

Sternberg RJ. Intelligence. Dialogues Clin Neurosci. 2012 Mar;14(1):19-27. Review.

PubMed: 22577301. Free full-text available from PubMed Central: PMC3341646

To find out more about the influence of genetics on intelligence:

The Tech Museum of Innovation at Stanford University provides a Q&A about the
influence of genes and environment on IQ (https://genetics.thetech.org/ask-a-geneticist/i
ntelligence-and-genetics).

Cambridge Brain Sciences discusses a recent research study that identified 22 genes
that have been linked to intelligence (https://www.cambridgebrainsciences.com/more/art
icles/22-genes-have-been-linked-to-intelligence). (See Sniekers, et al (2017) in the '
scientific journal articles for further reading' list in the main summary to read the full
research study.)

The Cold Spring Harbor Laboratory offers an interactive tool called Genes to Cognition (
https://dnalc.cshl.edu/view/2251-Thinking-.html) that provides information about many
aspects of the genetics of neuroscience.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 103

 5.4 Is handedness determined by genetics?
Like most aspects of human traits, handedness is complex and appears to be
influenced by multiple factors, including genetics and environment.

Handedness, or hand preference, is the tendency to be more skilled and comfortable

using one hand instead of the other for tasks such as writing and throwing a ball.
Although the percentage varies worldwide, in Western countries, 85 to 90 percent of
people are right-handed and 10 to 15 percent of people are left-handed. Mixed-
handedness (preferring different hands for different tasks) and ambidextrousness (the
ability to perform tasks equally well with either hand) are uncommon.

Hand preference becomes increasingly apparent in early childhood and tends to be

consistent throughout life. However, little is known about its biological basis. Hand
preference probably arises as part of the developmental process that differentiates the
right and left sides of the body (called right-left asymmetry). More specifically,
handedness appears to be related to differences between the right and left halves
(hemispheres) of the brain. The right hemisphere controls movement on the left side of
the body, while the left hemisphere controls movement on the right side of the body.

It was initially thought that a single gene controlled handedness. However, more recent
studies suggest that multiple genes, perhaps up to 40, contribute to this trait. Each of
these genes likely has a weak effect by itself, but together they play a significant role in
establishing hand preference. Studies suggest that at least some of these genes help
determine the overall right-left asymmetry of the body starting in the earliest stages of
development. So far, researchers have identified only a few of the many genes thought
to influence handedness. Studies suggest that other factors also contribute to
handedness. The prenatal environment and cultural influences may play a role.

Like many complex traits, handedness does not have a simple pattern of inheritance.
Children of left-handed parents are more likely to be left-handed than are children of
right-handed parents. However, because the overall chance of being left-handed is
relatively low, most children of left-handed parents are right-handed. Identical twins are
more likely than non-identical twins (or other siblings) to both be right-handed or left-
handed, but many twins have opposite hand preferences.

Scientific journal articles for further reading

Armour JA, Davison A, McManus IC. Genome-wide association study of handedness
excludes simple genetic models. Heredity (Edinb). 2014 Mar;112(3):221-5. doi:10.1038/
hdy.2013.93. Epub 2013 Sep 25. PubMed: 24065183. Free full-text available from
PubMed Central: PMC3931166.

Brandler WM, Morris AP, Evans DM, Scerri TS, Kemp JP, Timpson NJ, St Pourcain B,
Smith GD, Ring SM, Stein J, Monaco AP, Talcott JB, Fisher SE, Webber C, Paracchini
S. Common variants in left/right asymmetry genes and pathways are associated with
relative hand skill. PLoS Genet. 2013;9(9):e1003751. doi: 10.1371/journal.pgen.
1003751. Epub 2013 Sep 12. PubMed: 24068947. Free full-text available from PubMed

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 104

Central: PMC3772043.

Brandler WM, Paracchini S. The genetic relationship between handedness and

neurodevelopmental disorders. Trends Mol Med. 2014 Feb;20(2):83-90. doi: 10.1016/j.
molmed.2013.10.008. Epub 2013 Nov 23. Review. PubMed: 24275328. Free full-text
available from PubMed Central: PMC3969300

de Kovel CGF, Francks C. The molecular genetics of hand preference revisited. Sci
Rep. 2019 Apr 12;9(1):5986. doi: 10.1038/s41598-019-42515-0. PubMed: 30980028;
Free full-text available from PubMed Central: PMC6461639.

McManus IC, Davison A, Armour JA. Multilocus genetic models of handedness closely
resemble single-locus models in explaining family data and are compatible with genome-
wide association studies. Ann N Y Acad Sci. 2013 Jun;1288:48-58. doi:10.1111/nyas.
12102. Epub 2013 Apr 30. PubMed: 23631511. Free full-text available from PubMed
Central: PMC4298034.

To find out more about how handedness is determined:

General information about left-handedness, including its causes, is available from the
Better Health Channel (https://www.betterhealth.vic.gov.au/health/healthyliving/left-hand
edness) (Australia).

The Washington State Twin Registry has an FAQ about hand preference in identical
twins (https://wstwinregistry.org/2015/10/01/do-identical-twins-always-have-the-same-h
and-preference/).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 105

 5.5 Is the probability of having twins determined by genetics?

The likelihood of conceiving twins is a complex trait, meaning that it is affected by

multiple genetic and environmental factors, depending on the type of twins. The two
types of twins are classified as monozygotic and dizygotic.

Monozygotic (MZ) twins, also called identical twins, occur when a single egg cell is
fertilized by a single sperm cell. The resulting zygote splits into two very early in
development, leading to the formation of two separate embryos. MZ twins occur in 3 to
4 per 1,000 births worldwide. Research suggests that most cases of MZ twinning are
not caused by genetic factors. However, a few families with a larger-than-expected
number of MZ twins have been reported, which indicates that genetics may play a role.
It is possible that genes involved in sticking cells together (cell adhesion) may contribute
to MZ twinning, although this hypothesis has not been confirmed. Most of the time, the
cause of MZ twinning is unknown.

Dizygotic (DZ) twins, also called fraternal twins, occur when two egg cells are each
fertilized by a different sperm cell in the same menstrual cycle. DZ twins are about twice
as common as MZ twins, and they are much more likely to run in families. Compared to
the general population, having DZ twins is about two times more likely if a close relative
(for example, a sister) has had DZ twins.

DZ twinning is thought to be a result of hyperovulation, which is the release of more

than one egg in a single menstrual cycle. To explain how DZ twinning can run in
families, researchers have looked for genetic factors that increase the chance of
hyperovulation. However, studies examining the contributions of specific genes have
had mixed and conflicting results. Few specific genes in humans have been definitively
linked with hyperovulation or an increased probability of DZ twinning.

Other factors known to influence the chance of having DZ twins include the mother’s
age, ethnic background, diet, body type, and number of other children. Assisted
reproductive technologies such as in vitro fertilization (IVF) are also associated with an
increased frequency of DZ twins.

Scientific journal articles for further reading

Hoekstra C, Zhao ZZ, Lambalk CB, Willemsen G, Martin NG, Boomsma DI,
Montgomery GW. Dizygotic twinning. Hum Reprod Update. 2008 Jan-Feb;14(1):37-47.
Epub 2007 Nov 16. Review. PubMed: 18024802.

Machin G. Familial monozygotic twinning: a report of seven pedigrees. Am J Med Genet

C Semin Med Genet. 2009 May 15;151C(2):152-4. doi: 10.1002/ajmg.c.30211. PubMed:
19363801.

Mbarek H, Steinberg S, Nyholt DR, Gordon SD, Miller MB, McRae AF, Hottenga JJ,
Day FR, Willemsen G, de Geus EJ, Davies GE, Martin HC, Penninx BW, Jansen R,
McAloney K, Vink JM, Kaprio J, Plomin R, Spector TD, Magnusson PK, Reversade B,

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 106

Harris RA, Aagaard K, Kristjansson RP, Olafsson I, Eyjolfsson GI, Sigurdardottir O, Iacono
WG, Lambalk CB, Montgomery GW, McGue M, Ong KK, Perry JR, Martin NG,
Stefánsson H, Stefánsson K, Boomsma DI. Identification of Common Genetic Variants
Influencing Spontaneous Dizygotic Twinning and Female Fertility. Am J Hum Genet.
2016 May 5;98(5):898-908. doi: 10.1016/j.ajhg.2016.03.008. Epub 2016 Apr 28.
PubMed: 27132594.

Monden C, Pison G, Smits J. Twin Peaks: more twinning in humans than ever before.
Hum Reprod. 2021 May 17;36(6):1666-1673. doi: 10.1093/humrep/deab029. PubMed:
33709110. Free full-text available from PubMed Central: PMC8129593.

Painter JN, Willemsen G, Nyholt D, Hoekstra C, Duffy DL, Henders AK, Wallace L,
Healey S, Cannon-Albright LA, Skolnick M, Martin NG, Boomsma DI, Montgomery GW.
A genome wide linkage scan for dizygotic twinning in 525 families of mothers of
dizygotic twins. Hum Reprod. 2010 Jun;25(6):1569-80. doi: 10.1093/humrep/deq084.
Epub 2010 Apr 8. PubMed: 20378614. Free full-text available from PubMed Central:
PMC2912534.

Shur N. The genetics of twinning: from splitting eggs to breaking paradigms. Am J Med
Genet C Semin Med Genet. 2009 May 15;151C(2):105-9. doi: 10.1002/ajmg.c.30204.
PubMed: 19363800.

To learn more about the genetics of twinning:

Information about factors influencing MZ and DZ twinning is available from the
Washington State Twin Registry:
• Twins run in my family. Do I have an increased chance of having twins? (https://wst
winregistry.org/2015/10/01/twins-run-in-my-family-do-i-have-an-increased-chance-of
-having-twins/)
• I am a twin. Do I have an increased chance of having twins? (https://wstwinregistry.
org/2015/10/01/i-am-a-twin-do-i-have-an-increased-chance-of-having-twins/)
• Does identical (MZ) twinning run in families? (https://wstwinregistry.org/2015/10/01/
does-mz-twinning-run-in-families/)
• What factors are related to fraternal (DZ) twinning? (https://wstwinregistry.org/2015/
10/01/what-factors-are-related-to-dz-twinning/)

The Tech Museum of Innovation at Stanford University offers a discussion of why twins
can run in families (https://genetics.thetech.org/ask-a-geneticist/twin-genetics).

A brief overview of the factors that influence twinning (https://www.nhs.uk/conditions/pre

gnancy-and-baby/twins-healthy-multiple-pregnancy/) is available from the UK National
Health Service.

More detailed information about genetic factors related to MZ twinning (http://www.omim

.org/entry/276410) and DZ twinning (http://www.omim.org/entry/276400) is available
from OMIM.org.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 107

 5.6 Is hair texture determined by genetics?
Genetic factors appear to play a major role in determining hair texture—straight, wavy,
or curly—and the thickness of individual strands of hair. Studies suggest that different
genes influence hair texture and thickness in people of different ethnic backgrounds.
For example, normal variations (polymorphisms) in two genes, EDAR and FGFR2, have
been associated with differences in hair thickness in Asian populations. A polymorphism
in another gene, TCHH, appears to be related to differences in hair texture in people of
northern European ancestry. It is likely that many additional genes contribute to hair
texture and thickness in various populations.

Several genetic syndromes are characterized by unusual hair texture. These syndromes
are caused by variants in genes that play roles in hair structure and stability, including
genes associated with specialized cell structures call desmosomes that hold hair cells
together, proteins called keratins that provide strength and resilience to hair strands,
and chemical signaling pathways involving a molecule called lysophosphatidic acid
(LPA), which promotes hair growth. Genetic syndromes that feature altered hair texture
include:
• Autosomal recessive hypotrichosis (caused by variants in the DSG4, LIPH, or
LPAR6 gene)
• Keratoderma with woolly hair (caused by variants in the JUP, DSP, DSC2, or
KANK2 gene)
• Monilethrix (caused by variants in the DSG4, KRT81, KRT83, or KRT86 gene)
• Uncombable hair syndrome (caused by variants in the PADI3, TCHH, or TGM3
gene)

Researchers speculate that the genes associated with these disorders probably also
contribute to normal variations in hair texture and thickness.

Factors other than genetics can also influence hair texture and thickness. Hormones,
certain medications, and chemicals such as hair relaxers or perms can alter the
characteristics of a person’s hair. These changes can be temporary or permanent. Hair
texture and thickness can also change with age.

Scientific journal articles for further reading

Fujimoto A, Kimura R, Ohashi J, Omi K, Yuliwulandari R, Batubara L, Mustofa MS,
Samakkarn U, Settheetham-Ishida W, Ishida T, Morishita Y, Furusawa T, Nakazawa M,
Ohtsuka R, Tokunaga K. A scan for genetic determinants of human hair morphology:
EDAR is associated with Asian hair thickness. Hum Mol Genet. 2008 Mar 15;17(6):835-
43. Epub 2007 Dec 8. PubMed: 18065779.

Fujimoto A, Nishida N, Kimura R, Miyagawa T, Yuliwulandari R, Batubara L, Mustofa

MS, Samakkarn U, Settheetham-Ishida W, Ishida T, Morishita Y, Tsunoda T, Tokunaga
K, Ohashi J. FGFR2 is associated with hair thickness in Asian populations. J Hum
Genet. 2009 Aug;54(8):461-5. doi: 10.1038/jhg.2009.61. Epub 2009 Jul 10. PubMed:

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 108

19590514.

Medland SE, Nyholt DR, Painter JN, McEvoy BP, McRae AF, Zhu G, Gordon SD,
Ferreira MA, Wright MJ, Henders AK, Campbell MJ, Duffy DL, Hansell NK, Macgregor S,
Slutske WS, Heath AC, Montgomery GW, Martin NG. Common variants in the
trichohyalin gene are associated with straight hair in Europeans. Am J Hum Genet.
2009 Nov;85(5):750-5. doi: 10.1016/j.ajhg.2009.10.009. Epub 2009 Nov 5. PubMed:
19896111. Free full-text from PubMed Central: PMC2775823.

Shimomura Y, Christiano AM. Biology and genetics of hair. Annu Rev Genomics Hum
Genet. 2010;11:109-32. doi: 10.1146/annurev-genom-021610-131501. Review.
PubMed: 20590427.

To find out more about the influence of genetics on hair texture:

The Tech Museum of Innovation at Stanford University provides a Q&A on the
differences in hair texture among ethnic groups (https://genetics.thetech.org/ask/ask107
) and another on the inheritance of hair texture (https://genetics.thetech.org/ask/ask368).

More detailed information about the genetics of hair thickness (http://omim.org/entry/612

630) and hair texture (http://omim.org/entry/139450) is available from OMIM.org.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 109

 5.7 Is hair color determined by genetics?
Hair color is determined by the amount of a pigment called melanin in hair. An
abundance of one type of melanin, called eumelanin, gives people black or brown hair.
An abundance of another pigment, called pheomelanin, gives people red hair.

Black. Large amount of eumelanin

Brown. Moderate amount of eumelanin

Blond. Very little eumelanin

Red. Mostly pheomelanin with a little eumelanin

The type and amount of melanin in hair is determined by many genes, although little is
known about most of them. The best-studied hair-color gene in humans is called MC1R.
This gene provides instructions for making a protein called the melanocortin 1 receptor,
which is involved in the pathway that produces melanin. The melanocortin 1 receptor
controls which type of melanin is produced by melanocytes. When the receptor is turned
on (activated), it triggers a series of chemical reactions inside melanocytes that
stimulate these cells to make eumelanin. If the receptor is not activated or is blocked,
melanocytes make pheomelanin instead of eumelanin. Many other genes also help to
regulate this process. Most people have two functioning copies of the MC1R gene, one
inherited from each parent. These individuals have black or brown hair, because of the
high amount of eumelanin. It is estimated that more than 90 percent of people in the
world have brown or black hair.

Some people have variations in one copy of the MC1R gene in each cell that causes
the gene to be turned off (deactivated). This type of genetic change is described as loss-
of-function. For these individuals, eumelanin production is lower, while pheomelanin
production is higher, so they have strawberry blond, auburn, or red hair. In an even
smaller percentage of people, both copies of the MC1R gene in each cell have loss-of-
function changes, and the melanin-production pathway produces only the pheomelanin
pigment. The hair of these individuals is almost always very red. Even when the melanin-
production pathway is making eumelanin, changes in other genes can reduce the
amount of eumelanin produced. These changes lead to blond hair.

Hair color ranges across a wide spectrum of hues, from flaxen blond to coal black.
Many genes other than MC1R play a role in determining shades of hair color by
controlling levels of eumelanin and pheomelanin. Some of these genes, including ASIP,
DTNBP1, GPR143, HPS3, KITLG, MLPH, MYO5A, MYO7A, OCA2, SLC45A2,
SLC24A5, TYRP1, TYR, ERCC6, GNAS, HERC2, IRF4, OBSCN, SLC24A4, TPCN2,
and MITF, are involved in the production of melanin in hair. Some of these genes are
associated with gene transcription (which is the first step in protein production), DNA
repair, the transport of substances (such as calcium) across cell membranes, or the
structure of hair follicles. Several of these genes contribute to eye and skin color, but

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 110

the exact role they play in determining hair color is unknown.

Hair color may change over time. Particularly in people of European descent, light hair
color may darken as individuals grow older. For example, blond-haired children often
have darker hair by the time they are teenagers. Researchers speculate that certain hair-
pigment proteins are activated as children grow older, perhaps in response to hormonal
changes that occur near puberty. Almost everyone’s hair will begin to turn gray as they
age, although when it happens and to what extent is variable. Gray hair is partly
hereditary and may vary by ethnic origin; it is also somewhat dependent on external
factors such as stress. Hair becomes gray when the hair follicle loses its ability to make
melanin, but exactly why that occurs is not clear.

Scientific journal articles for further reading

Branicki W, Liu F, van Duijn K, Draus-Barini J, Pospiech E, Walsh S, Kupiec T, Wojas-
Pelc A, Kayser M. Model-based prediction of human hair color using DNA variants. Hum
Genet. 2011 Apr;129(4):443-54. doi: 10.1007/s00439-010-0939-8. Epub 2011 Jan 4.
PubMed: 21197618. Free full-text available from PubMed Central: PMC3057002.

Commo S, Gaillard O, Thibaut S, Bernard BA. Absence of TRP-2 in melanogenic

melanocytes of human hair. Pigment Cell Res. 2004 Oct;17(5):488-97. PubMed:
15357835.

Han J, Kraft P, Nan H, Guo Q, Chen C, Qureshi A, Hankinson SE, Hu FB, Duffy DL,
Zhao ZZ, Martin NG, Montgomery GW, Hayward NK, Thomas G, Hoover RN, Chanock
S, Hunter DJ. A genome-wide association study identifies novel alleles associated with
hair color and skin pigmentation. PLoS Genet. 2008 May 16;4(5):e1000074. doi: 10.
1371/journal.pgen.1000074. PubMed: 18483556. Free full-text available from PubMed
Central: PMC2367449.

Ito S, Wakamatsu K. Diversity of human hair pigmentation as studied by chemical

analysis of eumelanin and pheomelanin. J Eur Acad Dermatol Venereol. 2011 Dec;
25(12):1369-80. doi: 10.1111/j.1468-3083.2011.04278.x. PubMed: 22077870.

Liu F, Wen B, Kayser M. Colorful DNA polymorphisms in humans. Semin Cell Dev Biol.
2013 Jun-Jul;24(6-7):562-75. doi: 10.1016/j.semcdb.2013.03.013. Epub 2013 Apr 12.
PubMed: 23587773.

Schaffer JV, Bolognia JL. The melanocortin-1 receptor: red hair and beyond. Arch
Dermatol. 2001 Nov;137(11):1477-85. PubMed: 11708951.

Siewierska-Górska A, Sitek A, Zadzinska E, Bartosz G, Strapagiel D. Association of five

SNPs with human hair colour in the Polish population. Homo. 2017 Mar;68(2):134-144.
doi: 10.1016/j.jchb.2017.02.002. Epub 2017 Feb 4. PubMed: 28242083.

Sturm RA. Molecular genetics of human pigmentation diversity. Hum Mol Genet. 2009
Apr 15;18(R1):R9-17. doi: 10.1093/hmg/ddp003. PubMed: 19297406.

Tobin DJ. Human hair pigmentation--biological aspects. Int J Cosmet Sci. 2008 Aug;

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 111

30(4):233-57. doi: 10.1111/j.1468-2494.2008.00456.x. PubMed: 18713071.

To find out more about the influence of genetics on hair color:

The Tech Interactive at Stanford University provides a Q&A page about hair color.
(https://www.thetech.org/ask-a-geneticist/hair-color-genetics)

KidsHealth from Nemours explains why hair turns gray (https://kidshealth.org/en/kids/gr

ay-hair.html?ref=search&WT.ac=msh-p-dtop-en-search-clk).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 112

 5.8 Is height determined by genetics?
Scientists estimate that about 80 percent of an individual’s height is determined by the
DNA sequence variations they have inherited, but which genes these changes are in
and what they do to affect height are only partially understood. Some rare gene variants
have dramatic effects on height (for example, variants in the FGFR3 gene cause
achondroplasia, a rare condition characterized by short stature). For most individuals,
though, height is controlled largely by a combination of genetic variants that each have
more modest effects on height, plus a smaller contribution from environmental factors
(such as nutrition). More than 700 such gene variants have been discovered and many
more are expected to be identified. Some of these variants are in genes that directly or
indirectly affect cartilage in growth plates, which are areas in the long bones of the legs
and arms where new bone is produced, lengthening the bones as children grow. The
function of many other height-associated genes remains unknown.

In addition to the FGFR3 gene, researchers have identified hundreds of other genes
involved in rare disorders that have an extreme effect on height. These genes (and the
conditions they are associated with) include FBN1 (acromicric dysplasia, geleophysic
dysplasia, Marfan syndrome), GH1 (isolated growth hormone deficiency), EVC (Ellis-
van Creveld syndrome), Weyers acrofacial dysostosis), and GPC3 (Simpson-Golabi-
Behmel syndrome). By studying the dramatic effect that altered versions of these genes
have on height, scientists hope to better understand the complex interactions among
genes that contribute to normal height. Some genes, such as ACAN, contain rare
variants that cause severe growth disorders, and also other variants with milder effects
on height in individuals without a related health condition. Identifying other height genes,
and variants with large or small effects, is an active area of genetic research.

Because height is determined by multiple gene variants (an inheritance pattern called
polygenic inheritance), it is difficult to accurately predict how tall a child will be. The
inheritance of these variants from one’s parents helps explain why children usually grow
to be approximately as tall as their parents, but different combinations of variants can
cause siblings to be of different heights. Height is influenced by other biological
mechanisms (such as hormones) that may also be determined by genetics, although
the roles of these mechanisms are not fully understood.

In addition to genetic and biological determinants, height is also influenced by

environmental factors, including a mother's nutrition during pregnancy, whether she
smoked, and her exposure to hazardous substances. A well-nourished, healthy, and
active child is likely to be taller as an adult than will be a child with a poor diet, infectious
diseases, or inadequate health care. Socioeconomic factors such as income, education,
and occupation can also influence height. In some cases, ethnicity plays a role in adult
height, but studies on immigrant families have shown that moving to a country with
better access to nutritious food, healthcare, and employment opportunities can have a
substantial influence on the height of the next generation; this suggests that some
differences in height between ethnicities are explained by non-genetic factors.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 113

Scientific journal articles for further reading
Lango Allen H, Estrada K, Lettre G, et al. Hundreds of variants clustered in genomic loci
and biological pathways affect human height. Nature. 2010 Oct 14;467(7317):832-8. doi:
10.1038/nature09410. Epub 2010 Sep 29. PubMed: 20881960. Free full-text available
from PubMed Central: PMC2955183.

Marouli E, Graff M, Medina-Gomez C, Lo KS, et al. Rare and low-frequency coding

variants alter human adult height. Nature. 2017 Feb 9;542(7640):186-190. doi: 10.1038/
nature21039. Epub 2017 Feb 1. PubMed: 28146470. Free full-text available from
PubMed Central: PMC5302847.

McEvoy BP, Visscher PM. Genetics of human height. Econ Hum Biol. 2009 Dec;7(3):
294-306. doi: 10.1016/j.ehb.2009.09.005. Epub 2009 Sep 17. PubMed: 19818695.

Perola M. Genome-wide association approaches for identifying loci for human height
genes. Best Pract Res Clin Endocrinol Metab. 2011 Feb;25(1):19-23. doi: 10.1016/j.
beem.2010.10.013. PubMed: 21396572.

To learn more about the genetics of height:

The Broad Institute of the Massachusetts Institute of Technology and Harvard University
published a press release about the Genetic Investigation of Anthropometric Traits
(GIANT) study (https://www.broadinstitute.org/news/giant-study-reveals-giant-number-g
enes-linked-height), which greatly expanded understanding of the role of genetics in
height determination.

OMIM.org provides a list of genes that are associated with height (https://www.omim.org
/search/?index=geneMap&search=stature+height+shortness+tallness&start=1
&limit=10).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 114

 5.9 Are moles determined by genetics?
Moles are very common, especially in people with fair skin. Moles are overgrowths of
skin cells called melanocytes, but the genetic factors involved in their development are
not well understood. Although moles, like tumors, are an overgrowth of cells, moles are
almost always noncancerous (benign). Perhaps because most moles are benign,
scientists have not studied them extensively, and not much is known about their
genetics. Similar numbers of moles seem to occur on individuals of different generations
of a family, so a tendency to develop moles seems to be inherited, but the inheritance
pattern is not well understood.Most moles occur on parts of the body that are exposed
to the sun (ultraviolet radiation), and the number of moles an individual has may
increase after extended time in the sun. Moles usually begin to occur in childhood.
These moles are called acquired melanocytic nevi (and include the subtype epidermal
nevus). It is common for new moles to appear during times when hormone levels
change, such as adolescence and pregnancy. During an individual’s lifetime, moles may
change in appearance; hair may grow out of them, and they can change in size and
shape, darken, fade, or disappear. Infants and the elderly tend to have the fewest moles.

Sometimes, moles are present at birth or develop during infancy. These moles, which
are called congenital nevi, are almost always benign. Rarely, a very large mole, called a
giant congenital melanocytic nevus, is present at birth. In rare cases, the most serious
type of skin cancer (called melanoma) may develop in this type of mole. Large,
irregularly shaped and colored moles called dysplastic nevi or atypical moles can occur
at any age. Although not common, they tend to be numerous, and they increase a
person’s risk of melanoma. Heredity contributes to the development of dysplastic nevi
and to having a higher-than-average number of benign moles. Spending a lot of time in
the sun can also increase the number of moles a person has. However, moles are often
found on areas of the body that are not exposed, which suggests that factors other than
ultraviolet radiation from the sun, perhaps hormones or other biologic processes, are
involved in triggering the development of acquired melanocytic nevi and dysplastic nevi.

Although the genetics of melanoma has been widely studied, much less is known about
genes involved in the development of benign moles. Variations in several genes,
including FGFR3, PIK3CA, HRAS, and BRAF, are involved with benign moles. The
most-studied of these is the BRAF gene. A variant in BRAF leads to the production of
an altered protein that causes melanocytes to aggregate into moles. This altered protein
also triggers the production of a tumor-suppressor protein called p15 that stops moles
from growing too big. In rare cases, BRAF gene variants together with loss (deletion) of
the CDKN2A gene causes a lack of p15, which creates the potential for mole cells to
grow uncontrollably and become cancerous (malignant). The formation of cancer is
increasingly likely when combined with environmental factors, such as cell damage
caused by ultraviolet radiation exposure.In susceptible individuals (those with fair skin,
light hair, skin that burns instead of tans, a family history of melanoma, and genetic risk
factors such as deletion of or variants in the CDKN2A gene), ultraviolet radiation from
repeated sun exposure can damage existing moles, increasing their risk of becoming

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 115

malignant. Research has shown that individuals who have an abundance of moles are at
an increased risk of melanoma. However, some people who are diagnosed with
melanoma have few moles, and melanoma often develops in areas of the body that are
not exposed to the sun. Researchers are working to identify additional susceptibility
genes to better understand the genetics of moles and their relationship with cancer.

Scientific journal
Plasmeijer EI, Nguyenarticles for
TM, Olsen further
CM, Janda reading
M, Soyer HP, Green AC. The natural
history of common melanocytic nevi: a systematic review of longitudinal studies in the
general population. J Invest Dermatol. 2017 Sep;137(9):2017-2018. doi: 10.1016/j.jid.
2017.03.040. Epub 2017 May 18. PubMed: 28528913.

Roh MR, Eliades P, Gupta S, Tsao H. Genetics of melanocytic nevi. Pigment Cell
Melanoma Res. 2015 Nov;28(6):661-72. doi: 10.1111/pcmr.12412. PubMed: 26300491.
Free full-text available from PubMed Central: PMC4609613.Silva JH1, Sá BC, Avila AL,
Landman G, Duprat Neto JP. Atypical mole syndrome and dysplastic nevi: identification
of populations at risk for developing melanoma - review article. Clinics (Sao Paulo).
2011;66(3):493-9. PubMed: 21552679. Free full-text available from PubMed Central:
PMC3072014.

To learn more about the genetics of moles:

MedlinePlus offers additional resources (https://medlineplus.gov/moles.html) to learn
more about moles.

A University of Pennsylvania press release describes BRAF and p15, factors that keep
moles from turning into melanoma (https://www.pennmedicine.org/news/news-releases/
2015/august/penn-scientists-identify-key-g).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 116

 5.10 Are facial dimples determined by genetics?
Dimples—indentations on the cheeks—tend to occur in families, and this trait is
assumed to be inherited. Dimples are usually considered a dominant genetic trait, which
means that one copy of the altered gene in each cell is sufficient to cause dimples.
However, some researchers say that there is no proof that dimples are inherited. Little
research has been done to explore the genetics of dimples and it is not known which
gene or genes may be involved.

A dimple is an anomaly of the muscle that causes a dent in the cheek, especially when
the individual smiles. Some people have dimples in both cheeks, others in just one
cheek. Babies are likely to have dimples caused by baby fat in their cheeks. When they
lose their baby fat as they get older, their dimples disappear. Other children do not
have them at birth but may develop them later in childhood. In some people, dimples
last only until adolescence or young adulthood, while in others they are a lifetime trait.

Dimples that have a similar appearance can occur in successive generations of a family.
For example, in one family, it was observed that the siblings, their father, uncles,
grandfather, and great-grandfather all had similar-looking dimples in both cheeks. In
other families, dimples may occur in a child but are not seen in more than one
generation.

Scientific articles for further reading

OMIM: Dimples, Facial (126100)

Wiedemann HR. Cheek dimples. Am J Med Genet. 1990 Jul;36(3):376. PubMed:

2363446.

To find out more about the influence of genetics on dimples:

Stanford at the Tech: Genetics of Dimples (https://genetics.thetech.org/ask/ask47)

Genetic Science Learning Center at the University of Utah: Observable Human

Characteristics (https://learn.genetics.utah.edu/content/basics/observable/)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 117

 5.11 Is athletic performance determined by genetics?
Athletic performance is a complex trait that is influenced by both genetic and
environmental factors. Many physical traits help determine an individual’s athletic ability,
primarily the strength of muscles used for movement (skeletal muscles) and the
predominant type of fibers that compose them. Skeletal muscles are made up of two
types of muscle fibers: slow-twitch fibers and fast-twitch fibers. Slow-twitch muscle
fibers contract slowly but can work for a long time without tiring; these fibers enable
endurance activities like long-distance running. Fast-twitch muscle fibers contract
quickly but tire rapidly; these fibers are good for sprinting and other activities that
require power or strength. Other traits related to athleticism include the maximum
amount of oxygen the body can deliver to its tissues (aerobic capacity), muscle mass,
height, flexibility, coordination, intellectual ability, and personality.

Studies focused on similarities and differences in athletic performance within families,

including between twins, suggest that genetic factors underlie 30 to 80 percent of the
differences among individuals in traits related to athletic performance. Many studies
have investigated variations in specific genes thought to be involved in these traits,
comparing athletes with nonathletes.

The best-studied genes associated with athletic performance are ACTN3 and ACE.
These genes influence the fiber type that makes up muscles, and they have been linked
to strength and endurance. The ACTN3 gene provides instructions for making a protein
called alpha (α)-actinin-3, which is predominantly found in fast-twitch muscle fibers. A
variant in this gene, called R577X, leads to production of an abnormally short α-actinin-
3 protein that is quickly broken down. Some people have this variant in both copies of
the gene; this genetic pattern (genotype) is referred to as 577XX. These individuals
have a complete absence of α-actinin-3, which appears to reduce the proportion of fast-
twitch muscle fibers and increase the proportion of slow-twitch fibers in the body. Some
studies have found that the 577XX genotype is more common among high-performing
endurance athletes (for example, cyclists and long-distance runners) than in the general
population, while other studies have not supported these findings. The 577RR genotype
is associated with a high proportion of fast-twitch fibers and is seen more commonly in
athletes who rely on strength or speed, such as short-distance runners.

The ACE gene provides instructions for making a protein called angiotensin-converting
enzyme, which converts a hormone called angiotensin I to another form called
angiotensin II. Angiotensin II helps control blood pressure and may also influence
skeletal muscle function, although this role is not completely understood. A variation in
the ACE gene, called the ACE I/D polymorphism, alters activity of the gene. Individuals
can have two copies of a version called the D allele, which is known as the DD pattern,
two copies of a version called the I allele, known as the II pattern, or one copy of each
version, called the ID pattern. Of the three patterns, DD is associated with the highest
levels of angiotensin-converting enzyme. The DD pattern is thought to be related to a
higher proportion of fast-twitch muscle fibers and greater speed.

Many other genes with diverse functions have been associated with athletic
performance. Some are involved in the function of skeletal muscles, while others play

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 118

roles in the production of energy for cells, communication between nerve cells, or other
cellular processes.

Other studies have examined variations across the entire genomes (an approach called
genome-wide association studies or GWAS) of elite athletes to determine whether
specific areas of the genome are associated with athleticism. More than 150 different
variations linked to athletic performance have been identified in these studies; however,
most have been found in only one or a few studies, and the significance of most of
these genetic changes have not been identified. It is likely that a large number of genes
are involved, each of which makes only a small contribution to athletic performance.

Athletic performance is also strongly influenced by the environment. Factors such as the
amount of support a person receives from family and coaches, economic and other
circumstances that allow one to pursue the activity, availability of resources, and a
person’s relative age compared to their peers all seem to play a role in athletic
excellence. A person’s environment and genes influence each other, so it can be
challenging to tease apart the effects of the environment from those of genetics. For
example, if a child and his or her parent excel at a sport, is that similarity due to genetic
factors passed down from parent to child, to similar environmental factors, or (most
likely) to a combination of the two? It is clear that both environmental and genetic
factors play a part in determining athletic ability.

Scientific journal articles for further reading

Ahmetov II, Egorova ES, Gabdrakhmanova LJ, Fedotovskaya ON. Genes and Athletic
Performance: An Update. Med Sport Sci. 2016;61:41-54. doi: 10.1159/000445240.
Epub 2016 Jun 10. Review. PubMed: 27287076.

Ahmetov II, Fedotovskaya ON. Current Progress in Sports Genomics. Adv Clin Chem.
2015;70:247-314. doi: 10.1016/bs.acc.2015.03.003. Epub 2015 Apr 11. Review.
PubMed: 26231489.

Webborn N, Williams A, McNamee M, Bouchard C, Pitsiladis Y, Ahmetov I, Ashley E,

Byrne N, Camporesi S, Collins M, Dijkstra P, Eynon N, Fuku N, Garton FC, Hoppe N,
Holm S, Kaye J, Klissouras V, Lucia A, Maase K, Moran C, North KN, Pigozzi F, Wang
G. Direct-to-consumer genetic testing for predicting sports performance and talent
identification: Consensus statement. Br J Sports Med. 2015 Dec;49(23):1486-91. doi:
10.1136/bjsports-2015-095343. PubMed: 26582191. Free full-text available from
PubMed Central: PMC4680136.

Yan X, Papadimitriou I, Lidor R, Eynon N. Nature versus Nurture in Determining Athletic

Ability. Med Sport Sci. 2016;61:15-28. doi: 10.1159/000445238. Epub 2016 Jun 10.
Review. PubMed: 27287074.

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 5.12 Is longevity determined by genetics?
The duration of human life (longevity) is influenced by genetics, the environment, and
lifestyle. Environmental improvements beginning in the 1900s extended the average life
span dramatically with significant improvements in the availability of food and clean
water, better housing and living conditions, reduced exposure to infectious diseases,
and access to medical care. Most significant were public health advances that reduced
premature death by decreasing the risk of infant mortality, increasing the chances of
surviving childhood, and avoiding infection and communicable disease. Now people in
the United States live about 80 years on average, but some individuals survive for much
longer.

Scientists are studying people in their nineties (called nonagenarians) and hundreds
(called centenarians, including semi-supercentenarians of ages 105-109 years and
supercentenarians, ages 110+) to determine what contributes to their long lives. They
have found that long-lived individuals have little in common with one another in
education, income, or profession. The similarities they do share, however, reflect their
lifestyles—many are nonsmokers, do not have obesity, and cope well with stress. Also,
most are women. Because of their healthy habits, these older adults are less likely to
develop age-related chronic diseases, such as high blood pressure, heart disease,
cancer, and diabetes, than their same-age peers.

The siblings and children (collectively called first-degree relatives) of long-lived

individuals are more likely to remain healthy longer and to live to an older age than their
peers. People with centenarian parents are less likely at age 70 to have the age-related
diseases that are common among older adults. The brothers and sisters of centenarians
typically have long lives, and if they develop age-related diseases (such as high blood
pressure, heart disease, cancer, or type 2 diabetes), these diseases appear later than
they do in the general population. Longer life spans tend to run in families, which
suggests that shared genetics, lifestyle, or both play an important role in determining
longevity.

The study of longevity genes is a developing science. It is estimated that about 25

percent of the variation in human life span is determined by genetics, but which genes,
and how they contribute to longevity, are not well understood. A few of the common
variations (called polymorphisms) associated with long life spans are found in the APOE,
FOXO3, and CETP genes, but they are not found in all individuals with exceptional
longevity. It is likely that variants in multiple genes, some of which are unidentified, act
together to contribute to a long life.

Whole genome sequencing studies of supercentenarians have identified the same gene
variants that increase disease risk in people who have average life spans. The
supercentenarians, however, also have many other newly identified gene variants that
possibly promote longevity. Scientists speculate that for the first seven or eight decades,
lifestyle is a stronger determinant of health and life span than genetics. Eating well, not
drinking too much alcohol, avoiding tobacco, and staying physically active enable some
individuals to attain a healthy old age; genetics then appears to play a progressively
important role in keeping individuals healthy as they age into their eighties and beyond.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 120

Many nonagenarians and centenarians are able to live independently and avoid age-
related diseases until the very last years of their lives.

Some of the gene variants that contribute to a long life are involved with the basic
maintenance and function of the body’s cells. These cellular functions include DNA
repair, maintenance of the ends of chromosomes (regions called telomeres), and
protection of cells from damage caused by unstable oxygen-containing molecules (free
radicals). Other genes that are associated with blood fat (lipid) levels, inflammation, and
the cardiovascular and immune systems contribute significantly to longevity because
they reduce the risk of heart disease (the main cause of death in older people), stroke,
and insulin resistance.

In addition to studying the very old in the United States, scientists are also studying a
handful of communities in other parts of the world where people often live into their
nineties and older—Okinawa (Japan), Ikaria (Greece), and Sardinia (Italy). These three
regions are similar in that they are relatively isolated from the broader population in their
countries, are lower income, have little industrialization, and tend to follow a traditional
(non-Western) lifestyle. Unlike other populations of the very old, the centenarians on
Sardinia include a significant proportion of men. Researchers are studying whether
hormones, sex-specific genes, or other factors may contribute to longer lives among
men as well as women on this island.

Scientific journal articles for further reading

Martin GM, Bergman A, Barzilai N. Genetic determinants of human health span and life
span: progress and new opportunities. PLoS Genet. 2007 Jul;3(7):e125. PubMed:
17677003. Free full-text available from PubMed Central: PMC1934400.

Sebastiani P, Gurinovich A, Bae H, Andersen S, Malovini A, Atzmon G, Villa F, Kraja AT,

Ben-Avraham D, Barzilai N, Puca A, Perls TT. Four genome-wide association studies
identify new extreme longevity variants. J Gerontol A Biol Sci Med Sci. 2017 Oct 12;
72(11):1453-1464. doi: 10.1093/gerona/glx027. PubMed: 28329165.

Sebastiani P, Solovieff N, Dewan AT, Walsh KM, Puca A, Hartley SW, Melista E,
Andersen S, Dworkis DA, Wilk JB, Myers RH, Steinberg MH, Montano M, Baldwin CT,
Hoh J, Perls TT. Genetic signatures of exceptional longevity in humans. PLoS One.
2012;7(1):e29848. doi: 10.1371/journal.pone.0029848. Epub 2012 Jan 18. PubMed:
22279548. Free full-text available from PubMed Central: PMC3261167.

Wei M, Brandhorst S, Shelehchi M, Mirzaei H, Cheng CW, Budniak J, Groshen S, Mack

WJ, Guen E, Di Biase S, Cohen P, Morgan TE, Dorff T, Hong K, Michalsen A, Laviano
A, Longo VD. Fasting-mimicking diet and markers/risk factors for aging, diabetes,
cancer, and cardiovascular disease. Sci Transl Med. 2017 Feb 15;9(377). pii: eaai8700.
doi: 10.1126/scitranslmed.aai8700. PubMed: 28202779.

Young RD. Validated living worldwide supercentenarians, living and recently deceased:
February 2018. Rejuvenation Res. 2018 Feb 1. doi: 10.1089/rej.2018.2057. [Epub
ahead of print] PubMed: 29390945.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 121

To learn more about the genetics of longevity:
Boston University School of Medicine provides a description of the New England
Centenarian Study (http://www.bumc.bu.edu/centenarian/).

The Institute for Aging Research at Albert Einstein College of Medicine describes the
Longevity Genes Project (https://www.einsteinmed.edu/centers/aging/longevity-genes-p
roject/about-the-study/).

The Duke University Center for Population Health & Aging provides descriptions of
studies of long lives (https://cpha.duke.edu/life-course-studies).

The National Institute on Aging offers a video about the Baltimore Longitudinal Study of
Aging (https://www.nia.nih.gov/research/labs/blsa/about).

The SardiNIA Project has several pages describing research investigating longevity
genes (https://sardinia.irp.nia.nih.gov/index.html) among Italians living on the
Mediterranean island of Sardinia.

The Okinawa Centenarian Study (https://orcls.org/) describes the genetics, healthy

aging, and longevity of Japanese living on the island of Okinawa.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 122

 5.13 Is temperament determined by genetics?
Temperament includes behavioral traits such as sociability (outgoing or shy),
emotionality (easy-going or quick to react), activity level (high or low energy), attention
level (focused or easily distracted), and persistence (determined or easily discouraged).
These examples represent a spectrum of common characteristics, each of which may
be advantageous in certain circumstances. Temperament remains fairly consistent,
particularly throughout adulthood.

Similar temperaments within a family may be attributable to shared genetics and to the
environment in which an individual is raised. Studies of identical twins (who share 100
percent of their DNA) and their non-twin siblings (who share about 50 percent of their
DNA) show that genetics play a large role. Identical twins typically have very similar
temperaments when compared with their other siblings. Even identical twins who were
raised apart from one another in separate households share such traits.

Scientists estimate that 20 to 60 percent of temperament is determined by genetics.

Temperament, however, does not have a clear pattern of inheritance and there are not
specific genes that confer specific temperamental traits. Instead, many (perhaps
thousands) of common gene variations (polymorphisms) combine to influence individual
characteristics of temperament. Other DNA modifications that do not alter DNA
sequences (epigenetic changes) also likely contribute to temperament.

Large studies have identified several genes that play a role in temperament. Many of
these genes are involved in communication between cells in the brain. Certain gene
variations may contribute to particular traits related to temperament. For example,
variants in the DRD2 and DRD4 genes have been linked to a desire to seek out new
experiences, and KATNAL2 gene variants are associated with self-discipline and
carefulness. Variants affecting the PCDH15 and WSCD2 genes are associated with
sociability, while some MAOA gene variants may be linked to introversion, particularly in
certain environments. Variants in several genes, such as SLC6A4, AGBL2, BAIAP2,
CELF4, L3MBTL2, LINGO2, XKR6, ZC3H7B, OLFM4, MEF2C, and TMEM161B
contribute to anxiousness or depression.

Environmental factors also play a role in temperament by influencing gene activity. In

children raised in an adverse environment (such as one of child abuse and violence),
genes that increase the risk of impulsive temperamental characteristics may be turned
on (activated). However, a child who grows up in a positive environment (for example a
safe and loving home) may have a calmer temperament, in part because a different set
of genes is activated

Scientific journal articles for further reading

Bratko D, Butkovic A, Vukasovic T. Heritability of personality. Psychological Topics, 26
(2017), 1, 1-24.

Manuck SB, McCaffery JM. Gene-environment interaction. Annu Rev Psychol. 2014;65:
41-70. doi: 10.1146/annurev-psych-010213-115100. PubMed: 24405358

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 123

Power RA, Pluess M. Heritability estimates of the big five personality traits based on
common genetic variants. Translational Psychiatry (2015) 5, e604; doi:10.1038/tp.2015.
96; published online 14 July 2015. PubMed: 26171985 PubMed Central: PMC5068715

To find out more about the role of genetics in temperament:

The Dana Foundation. One of a Kind: The Neurobiology of Individuality (https://www.da
na.org/article/one-of-a-kind-the-neurobiology-of-individuality/).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 124

 6
Genetic Consultation
6.1 What is a genetic consultation?
A genetic consultation is a health service that provides information and support to
people who have, or may be at risk for, genetic conditions. During a consultation, a
genetics professional meets with an individual or family to discuss genetic risks or to
diagnose, confirm, or rule out a genetic condition.

Genetics professionals include medical geneticists (doctors who specialize in genetics)

and genetic counselors (certified healthcare workers with experience in medical
genetics and counseling). Other healthcare professionals such as nurses, psychologists,
and social workers trained in genetics can also provide genetic consultations.

Consultations usually take place in a doctor’s office, hospital, genetics center, or other
type of medical center. These meetings are most often in-person visits with individuals
or families, but they are occasionally conducted in a group. Additionally, genetic
consultations may be carried out using telemedicine (also known as telehealth), in
which the meeting is done from a distance using computers, cameras,
videoconferencing tools, or the telephone.

For more information about genetic consultations:

MedlinePlus offers a list of links to information about genetic counseling (https://medline
plus.gov/geneticcounseling.html).

MedlinePlus also offers information about telehealth (https://medlineplus.gov/telehealth.

html).

Additional background information is provided by the National Human Genome

Research Institute in its Frequently Asked Questions About Genetic Counseling (https://
www.genome.gov/FAQ/Genetic-Counseling).

Information about genetic counseling, including the different types of counseling, is

available from the National Center for Biotechnology Information (NCBI) in the booklet
Making Sense of Your Genes: A Guide to Genetic Counseling (https://www.ncbi.nlm.nih
.gov/books/NBK115508/).

The National Society of Genetic Counselors discusses what happens during an

appointment (https://www.aboutgeneticcounselors.org/Prepare-for-an-Appointment/Wha
t-Happens-During-an-Appointment).

The Centre for Genetics Education also offers an introduction to genetic counseling (htt
ps://www.genetics.edu.au/publications-and-resources/facts-sheets/fact-sheet-6-genetic-
counselling).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 125

 6.2 Why might someone have a genetic consultation?
Individuals or families who are concerned about an inherited condition may benefit from
a genetic consultation. The reasons that a person might be referred to a genetic
counselor, medical geneticist, or other genetics professional include:
• A personal or family history of a genetic condition, birth defect, chromosomal
disorder, or hereditary cancer.
• Two or more pregnancy losses (miscarriages), a stillbirth, or a baby who died.
• A child with a known inherited disorder, a birth defect, intellectual disability, or
developmental delay.
• A woman who is pregnant or plans to become pregnant at or after age 35. (Some
chromosomal disorders occur more frequently in children born to older women.)
• Abnormal test results that suggest a genetic or chromosomal condition.
• An increased risk of developing or passing on a particular genetic disorder on the
basis of a person’s ethnic background.
• People related by blood (for example, cousins) who plan to have children together.
(A child whose parents are related may be at an increased risk of inheriting certain
genetic disorders.)
• A person received results from direct-to-consumer genetic testing and they want to
discuss the implications of the results.

A genetic consultation is also an important part of the decision-making process for

genetic testing. A visit with a genetics professional may be helpful even if testing is not
available for a specific condition, however.

For more information about the reasons for having a genetic

consultation:
An overview of indications for a genetics referral (https://www.ncbi.nlm.nih.gov/books/N
BK115554/) is available from The Genetic Alliance booklet "Understanding Genetics: A
Guide for Patients and Professionals."

The Centers for Disease Control and Prevention (CDC) Office of Public Health
Genomics has a list of reasons why people go for genetic counseling (https://www.cdc.g
ov/genomics/gtesting/genetic_counseling.htm).

The National Society of Genetic Counselors details the reasons to see a genetic
counselor, including pregnancy and family planning (https://www.aboutgeneticcounselor
s.org/Reasons-to-See-a-Genetic-Counselor/Pregnancy-and-Family-Planning), cancer (h
ttps://www.aboutgeneticcounselors.org/Reasons-to-See-a-Genetic-Counselor/Cancer),
childhood conditions (https://www.aboutgeneticcounselors.org/Reasons-to-See-a-Genet
ic-Counselor/Childhood-Conditions), and at-home genetic testing (https://www.aboutgen
eticcounselors.org/Reasons-to-See-a-Genetic-Counselor/At-Home-Genetic-Testing).

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 6.3 What happens during a genetic consultation?
A genetic consultation provides information, offers support, and addresses a patient’s
specific questions and concerns. To help determine whether a condition has a genetic
component, a genetics professional asks about a person’s medical history and takes a
detailed family health history (a record of health information about a person's immediate
and extended family). The genetics professional may also perform a physical
examination and recommend appropriate medical tests.

If a person is diagnosed with a genetic condition, the genetics professional provides

information about the diagnosis, how the condition is inherited, the chance of passing
the condition to future generations, and the options for testing and treatment.

During a consultation, a genetics professional will:

• Interpret and communicate complex medical information.
• Help each person make informed, independent decisions about their health care
and reproductive options.
• Respect each person’s individual beliefs, traditions, and feelings.

A genetics professional will NOT:

• Tell a person which decision to make.
• Coerce a couple about whether or not to have children.
• Recommend that a woman continue or end a pregnancy.
• Tell someone whether to undergo testing for a genetic disorder.

For more information about what to expect during a genetic

consultation:
The National Society of Genetic Counselors offers information about what to expect
from a genetic counseling session (https://www.aboutgeneticcounselors.org/Prepare-for
-an-Appointment/What-Happens-During-an-Appointment), what happens during a
prenatal genetic counseling appointment (https://www.aboutgeneticcounselors.org/Reas
ons-to-See-a-Genetic-Counselor/Pregnancy-and-Family-Planning), and insurance
coverage for genetic counseling (https://www.aboutgeneticcounselors.org/Prepare-for-a
n-Appointment/Insurance-Billing-and-Protecting-Your-Privacy).

Information about the role of genetic counselors and the process of genetic counseling (
https://www.ncbi.nlm.nih.gov/books/NBK115552/) are available from the Genetic
Alliance publication "Understanding Genetics: A Guide for Patients and Professionals."

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 127

 6.4 How can I find a genetics professional in my area?
To find a genetics professional in your community, you may wish to ask your doctor for
a referral. If you have health insurance, you can also contact your insurance company
to find a medical geneticist or genetic counselor in your area who participates in your
plan.

Several organizations have tips for finding a healthcare professional:

• The Genetic and Rare Diseases Information Center, a service of the National
Institutes of Health, provides a guide to finding specialists in particular genetic and
rare conditions.
• The Tuberous Sclerosis Alliance provides advice on finding and choosing a doctor.
Although this advice is written for adults with tuberous sclerosis, much of it applies to
people with any chronic health condition.

Additional resources for locating a genetics professional in your community are

available online:
• The National Society of Genetic Counselors (NSGC) offers a searchable directory
of genetic counselors in the United States and Canada. You can search by location,
name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (ABGC) provides a searchable
directory of certified genetic counselors worldwide. You can search by practice area,
name, organization, or location.
• The Canadian Association of Genetic Counsellors (CAGC) has a searchable
directory of genetic counselors in Canada. You can search by name, distance from
an address, province, or services.
• The American College of Medical Genetics and Genomics (ACMG) has a
searchable database of medical genetics clinic services in the United States.
• The National Cancer Institute provides a Cancer Genetics Services Directory, which
lists professionals who provide services related to cancer genetics. You can search
by type of cancer or syndrome, location, and/or provider name.

If you have a health condition that has not been diagnosed, you may be interested in
the Undiagnosed Diseases Network. They have information about how to apply for this
multicenter research study.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 128

 6.5 What is the prognosis of a genetic condition?
The prognosis of a genetic condition includes its likely course, duration, and outcome.
When health professionals refer to the prognosis of a disease, they may also mean the
chance of recovery; however, most genetic conditions are life-long and are managed
rather than cured.

Disease prognosis has multiple aspects, including:

• How long a person with the disorder is likely to live (life expectancy)
• When signs and symptoms develop and whether they worsen (and how quickly) or
are stable over time
• Quality of life, such as independence in daily activities
• Potential for complications and associated health issues

The prognosis of a genetic condition depends on many factors, including the specific
diagnosis and an individual's particular signs and symptoms. Sometimes the associated
genetic variant, if known, can also give clues to the prognosis. Additionally, the course
and outcome of a condition depends on the availability and effectiveness of treatment
and management approaches. The prognosis of very rare diseases can be difficult to
predict because so few affected individuals have been identified. Prognosis may also be
difficult or impossible to establish if a person's diagnosis is unknown.

The prognoses of genetic disorders vary widely, often even among people with the
same condition. This variability is likely caused by a combination of genetic,
environmental, and lifestyle factors, many of which can be difficult to identify.Some
genetic disorders cause physical and developmental problems that are so severe they
are incompatible with life. These conditions may cause a miscarriage of an affected
embryo or fetus, or an affected infant may be stillborn or die shortly after birth. People
with less severe genetic conditions may live into childhood or adulthood but have a
shortened lifespan due to health problems related to their disorder. Genetic conditions
with a milder course may be associated with a normal lifespan and few related health
issues.

The prognosis of a disease is based on probability, which means that it is likely but not
certain that the disorder will follow a particular course. Your healthcare provider is the
best resource for information about the prognosis of your specific genetic condition. He
or she can assess your medical history and signs and symptoms to give you the most
accurate estimate of your prognosis.

Learn more about the prognosis of genetic conditions:

MedlinePlus Genetics provides an additional list of resources that can help you locate a
genetics professional (https://medlineplus.gov/genetics/understanding/consult/findingpro
fessional/) in your area.

A discussion of the prognosis of disorders with a neurological basis (https://www.ninds.n

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ih.gov/Disorders/All-Disorders) is available from the National Institute of Neurological
Disorders and Stroke (NINDS).

The National Cancer Institute (NCI) provides an overview of cancer prognosis (https://w
ww.cancer.gov/about-cancer/diagnosis-staging/prognosis).

Local and national support and advocacy groups are also excellent resources for
information about specific genetic conditions, including disease prognosis. Patient
support resources related to specific genetic conditions can be identified through the
Genetic Alliance's Disease InfoSearch (https://www.diseaseinfosearch.org/).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 130

 6.6 How are genetic conditions diagnosed?
A doctor may suspect a diagnosis of a genetic condition on the basis of a person's
physical characteristics and family history, or on the results of a screening test.

Genetic testing is one of several tools that doctors use to diagnose genetic conditions.
The approaches to making a genetic diagnosis include:
• A physical examination: Certain physical characteristics, such as distinctive facial
features, can suggest the diagnosis of a genetic disorder. A geneticist will do a
thorough physical examination that may include measurements such as the distance
around the head (head circumference), the distance between the eyes, and the
length of the arms and legs. Depending on the situation, specialized examinations
such as nervous system (neurological) or eye (ophthalmologic) exams may be
performed. The doctor may also use imaging studies including x-rays, computerized
tomography (CT) scans, or magnetic resonance imaging (MRI) to see structures
inside the body.
• Personal medical history: Information about an individual's health, often going back
to birth, can provide clues to a genetic diagnosis. A personal medical history
includes past health issues, hospitalizations and surgeries, allergies, medications,
and the results of any medical or genetic testing that has already been done.
• Family health history: Because genetic conditions often run in families, information
about the health of family members can be a critical tool for diagnosing these
disorders. A doctor or genetic counselor will ask about health conditions in an
individual's parents, siblings, children, and possibly more distant relatives. This
information can give clues about the diagnosis and inheritance pattern of a genetic
condition in a family.
• Laboratory tests, including genetic testing: Molecular, chromosomal, and
biochemical genetic or genomic testing are used to diagnose genetic disorders.
Other laboratory tests that measure the levels of certain substances in blood and
urine can also help suggest a diagnosis.

Genetic testing is currently available for many genetic conditions. However, some
conditions do not have a genetic test; either the genetic cause of the condition is
unknown or a test has not yet been developed. In these cases, sequencing the entire
genome may result in locating the responsible genetic variant. Additionally, a
combination of the approaches listed above may be used to make a diagnosis. Even
when genetic testing is available, the tools listed above are used to narrow down the
possibilities (known as a differential diagnosis) and choose the most appropriate genetic
tests to pursue.

A diagnosis of a genetic disorder can be made anytime during life, from before birth to
old age, depending on when the features of the condition appear and the availability of
testing. Sometimes, having a diagnosis can guide treatment and management decisions.
A genetic diagnosis can also suggest whether other family members may be affected
by or at risk of a specific disorder. Even when no treatment is available for a particular
condition, having a diagnosis can help people know what to expect and may help them

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 131

identify useful support and advocacy resources.

For more information about diagnosing genetic conditions:

MedlinePlus Genetics provides additional information about genetic testing (https://medl
ineplus.gov/genetics/understanding/testing/) (https://medlineplus.gov/genetics/understa
nding/inheritance/familyhistory/).

The National Center for Biotechnology Information (NCBI) provides an in-depth guide
called Understanding Genetics (https://www.ncbi.nlm.nih.gov/books/NBK132142/),
which includes a chapter about how genetics professionals diagnose many types of
genetic disorders.

The Centers for Disease Control and Prevention (CDC) offers a fact sheet about the
diagnosis of birth defects (https://www.cdc.gov/ncbddd/birthdefects/diagnosis.html),
including information about screening and diagnostic test.

The American College of Medical Genetics offers practice guidelines, (https://www.acm

g.net/ACMG/Medical-Genetics-Practice-Resources/Practice-Guidelines.aspx) including
diagnostic criteria, for several genetic disorders. These guidelines are designed for
geneticists and other healthcare providers.

GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1116/), a resource from the

University of Washington and the NCBI, provides detailed information about the
diagnosis of specific genetic disorders as part of each peer-reviewed disease
description.

The Undiagnosed Diseases Network (https://undiagnosed.hms.harvard.edu/) is a

research study that helps people with diseases that have not been diagnosed. They
have information about applying to participate (https://undiagnosed.hms.harvard.edu/ap
ply/) in this study.

The Genetic and Rare Diseases Information Center (GARD), a service of the National
Institutes of Health, also provides tips for the undiagnosed (https://rarediseases.info.nih.
gov/guides/pages/24/tips-for-the-undiagnosed).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 132

 6.7 How are genetic conditions treated or managed?
Many genetic disorders result from gene changes that are present in essentially every
cell in the body. As a result, these disorders often affect many body systems, and most
cannot be cured. However, approaches may be available to treat or manage some of
the associated signs and symptoms.

For a group of genetic conditions called inborn errors of metabolism, which result from
genetic changes that disrupt the production of specific enzymes, treatments sometimes
include dietary changes or replacement of the particular enzyme that is missing.
Limiting certain substances in the diet can help prevent the buildup of potentially toxic
substances that are normally broken down by the enzyme. In some cases, enzyme
replacement therapy can help make up for the enzyme shortage. These treatments are
used to manage existing signs and symptoms and may help prevent future
complications. An example of an inborn error of metabolism is phenylketonuria (PKU).

For other genetic conditions, treatment and management strategies are designed to
improve particular signs and symptoms associated with the disorder. These approaches
vary by disorder and are specific to an individual's health needs. For example, a genetic
disorder associated with a heart defect might be treated with surgery to repair the defect
or with a heart transplant. Conditions that are characterized by defective blood cell
formation, such as sickle cell disease, can sometimes be treated with a bone marrow
transplant. Bone marrow transplantation can allow the formation of normal blood cells
and, if done early in life, may help prevent episodes of pain and other future
complications.

Some genetic changes are associated with an increased risk of future health problems,
such as certain forms of cancer. One well-known example is familial breast cancer
related to mutations in the BRCA1 and BRCA2 genes. Management may include more
frequent cancer screening or preventive (prophylactic) surgery to remove the tissues at
highest risk of becoming cancerous.

Genetic disorders may cause such severe health problems that they are incompatible
with life. In the most severe cases, these conditions may cause a miscarriage of an
affected embryo or fetus. In other cases, affected infants may be stillborn or die shortly
after birth. Although few treatments are available for these severe genetic conditions,
health professionals can often provide supportive care, such as pain relief or
mechanical breathing assistance, to the affected individual.

Most treatment strategies for genetic disorders do not alter the underlying genetic
mutation; however, a few disorders have been treated with gene therapy. This
experimental technique involves changing a person's genes to prevent or treat a
disease. Gene therapy, along with many other treatment and management approaches
for genetic conditions, are under study in clinical trials.

Find out more about the treatment and management of genetic

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 133

conditions:
GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1116/), a resource from the
University of Washington and the National Center for Biotechnology Information (NCBI),
provides detailed information about the management of specific genetic disorders as
part of each peer-reviewed disease description.

The Genetic and Rare Diseases Information Center, a service of the National Institutes
of Health, provides this video with suggestions for finding information about treatment (h
ttps://www.youtube.com/watch?v=by4nQriQcKs&list=PLtOMdJ_3bSnzIDTV_tD2q
OKLraENN9PLv&index=3) for genetic and rare conditions.

MedlinePlus provides additional information related to the treatment of genetic

conditions:
• Inborn Errors of Metabolism (https://medlineplus.gov/ency/article/002438.htm)
• Bone Marrow Transplantation (https://medlineplus.gov/bonemarrowtransplantation.
html)
• Palliative care (https://medlineplus.gov/palliativecare.html) (also known as
supportive care)
• Gene Therapy (https://medlineplus.gov/genetics/understanding/therapy/)
• Precision Medicine (https://medlineplus.gov/genetics/understanding/precisionmedici
ne/definition/)

The Fetal Treatment Center at the University of California, San Francisco describes
stem cell treatments for inherited diseases (https://fetus.ucsf.edu/stem-cells/).

ClinicalTrials.gov (https://clinicaltrials.gov/), a service of the National Institutes of Health,

provides easy access to information on clinical trials. You can search for specific trials
or browse by condition (https://www.clinicaltrials.gov/ct2/search/browse?brwse=cond_al
pha_all), trial sponsor (https://www.clinicaltrials.gov/ct2/search/browse?brwse=spns_cat
), location (https://www.clinicaltrials.gov/ct2/search/browse?brwse=locn_cat), or
treatment approach (for example, drug interventions (https://www.clinicaltrials.gov/ct2/s
earch/browse?brwse=intr_cat)).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 134

 7
Genetic Testing
7.1 What is genetic testing?
Genetic testing is a type of medical test that identifies changes in genes, chromosomes,
or proteins. The results of a genetic test can confirm or rule out a suspected genetic
condition or help determine a person’s chance of developing or passing on a genetic
disorder. More than 77,000 genetic tests are currently in use, and others are being
developed.

Genetic testing involves looking for changes in:

• Genes: Gene tests study DNA sequences to identify variations (mutations) in genes
that can cause or increase the risk of a genetic disorder. Gene tests can be narrow
or large in scope, analyzing an individual DNA building block (nucleotide), one or
more genes, or all of a person’s DNA (which is known as their genome).
• Chromosomes: Chromosomal genetic tests analyze whole chromosomes or long
lengths of DNA to see if there are large genetic changes, such as an extra copy of a
chromosome, that cause a genetic condition.
• Proteins: Biochemical genetic tests study the amount or activity level of proteins or
enzymes; abnormalities in either can indicate changes to the DNA that result in a
genetic disorder.

Genetic testing is voluntary. Because testing has benefits as well as limitations and
risks, the decision about whether to be tested is a personal and complex one. A
geneticist or genetic counselor can help by providing information about the pros and
cons of the test and discussing the social and emotional aspects of testing.

For general information about genetic testing:

MedlinePlus offers a list of links to information about genetic testing (https://medlineplus
.gov/genetictesting.html).

The Genetic Testing Registry (https://www.ncbi.nlm.nih.gov/gtr/) is a service from the

National Library of Medicine that provides a searchable database of genetic tests that
have submitted by providers and laboratories.

The National Human Genome Research Institute provides an overview of this topic in its
Frequently Asked Questions About Genetic Testing (https://www.genome.gov/FAQ/Gen
etic-Testing). Additional information about genetic testing legislation, policy, and
oversight (https://www.genome.gov/about-genomics/policy-issues/Regulation-of-Geneti
c-Tests) is available from the Institute.

You can also search for clinical trials involving genetic testing. ClinicalTrials.gov (https://
clinicaltrials.gov/), a service of the National Institutes of Health, provides easy access to
information on clinical trials. You can search for specific trials or browse by condition or

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 135

trial sponsor. You may wish to refer to a list of studies related to genetic testing (https://cli
nicaltrials.gov/search?term=%22genetic+testing%22) that are accepting (or will accept)
participants.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 136

 7.2 What are the different types of genetic tests?
Many types of genetic tests are available to analyze changes in genes, chromosomes,
or proteins. A health care provider will consider several factors when selecting the
appropriate test, including what condition or conditions are suspected and the genetic
variations typically associated with those conditions. If a diagnosis is unclear, a test that
looks at many genes or chromosomes may be used. However, if a specific condition is
suspected, a more focused test may be done.

There are several types of genetic tests:

Molecular tests look for changes in one or more genes. These types of tests determine
the order ofDNA (Figure 7.1) building blocks (nucleotides) in an individual's genetic
code, a process called DNA sequencing. These tests can vary in scope:
• Targeted single variant: Single variant tests look for a specific variant in one gene.
The selected variant is known to cause a disorder (for example, the specific variant
in the HBB gene that causes sickle cell disease). This type of test is often used to
test family members of someone who is known to have a particular variant, to
determine whether they have a familial condition. Also, direct-to-consumer genetic
testing companies typically analyze a number of specific variants in particular genes
(rather than finding all the variants in those genes) when providing health or disease
risk information.
• Single gene: Single gene tests look for any genetic changes in one gene. These
tests are typically used to confirm (or rule out) a specific diagnosis, particularly when
there are many variants in the gene that can cause the suspected condition.
• Gene panel: Panel tests look for variants in more than one gene. This type of test is
often used to pinpoint a diagnosis when a person has symptoms that may fit a wide
array of conditions, or when the suspected condition can be caused by variants in
many genes. (For example, there are hundreds of genetic causes of epilepsy.)
• Whole exome sequencing/whole genome sequencing: These tests analyze the bulk
of an individual’s DNA to find genetic variations. Whole exome or whole genome
sequencing is typically used when single gene or panel testing has not provided a
diagnosis, or when the suspected condition or genetic cause is unclear. Whole
exome or whole genome sequencing is often more cost- and time-effective than
performing multiple single gene or panel tests.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 137

 FIGURE 7.1: DNA is made up of base pairs and a sugar phosphate
backbone.

Chromosomal tests analyze whole chromosomes or long lengths of DNA to identify

large-scale changes. Changes that can be found include an extra or missing copy of a
chromosome (trisomy or monosomy, respectively), a large piece of a chromosome that
is added (duplicated) or missing (deleted), or rearrangements (translocations) of
segments of chromosomes. Certain genetic conditions are associated with specific
chromosomal changes, and a chromosomal test can be used when one of these
conditions is suspected. (For example, Williams syndrome is caused by a deletion of a
section of chromosome 7.)

Gene expression tests look at which genes are turned on or off (expressed) in different
types of cells. When a gene is turned on (active), the cell produces a molecule called
mRNA from the instructions in the genes, and the mRNA molecule is used as a
blueprint to make proteins. Gene expression tests study the mRNA in cells to determine
which genes are active. Too much activity (overexpression) or too little activity
(underexpression) of certain genes can be suggestive of particular genetic disorders,
such as many types of cancer.

Biochemical tests do not directly analyze DNA, but they study the amount or activity
level of proteins or enzymes that are produced from genes. Abnormalities in these

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 138

substances can indicate that there are changes in the DNA that underlie a genetic disorder.
(For example, low levels of biotinidase enzyme activity is suggestive of biotinidase
deficiency, which is caused by BTD gene variants.)

For information about types of genetic testing:

The Genetic Testing Registry (https://www.ncbi.nlm.nih.gov/gtr/) is available from the
National Center of Biotechnology and Information at the National Library of Medicine.
The Genetic Testing Registry is a database of laboratory-submitted genetic tests.

The Centers of Disease Control and Prevention provides a page discussing genetic
testing (https://www.cdc.gov/genomics/gtesting/genetic_testing.htm).

The Jackson Laboratory compares different types of genetic tests (https://www.jax.org/e

ducation-and-learning/clinical-and-continuing-education/cancer-resources/genetic-testin
g-technology-comparison).

GeneReviews compares whole genome sequencing, whole exome sequencing, and the
sequencing of a selection of individual genes (https://www.ncbi.nlm.nih.gov/books/NBK2
79899/), particularly their use in the diagnosis of genetic conditions.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 139

 7.3 What are the uses of genetic testing?
Genetic testing can provide information about a person's genetic background. The uses
of genetic testing include:

Newborn screening
Newborn screening is used just after birth to identify genetic disorders that can be
treated early in life. Millions of babies are tested each year in the United States. The U.
S. Health Services and Resource Administration recommends that states screen for a
set of 35 conditions, which many states exceed.

Diagnostic testing
Diagnostic testing is used to identify or rule out a specific genetic or chromosomal
condition. In many cases, genetic testing is used to confirm a diagnosis when a
particular condition is suspected based on physical signs and symptoms. Diagnostic
testing can be performed before birth or at any time during a person's life, but is not
available for all genes or all genetic conditions. The results of a diagnostic test can
influence a person's choices about health care and the management of the disorder.

Carrier testing
Carrier testing is used to identify people who carry one copy of a gene mutation that,
when present in two copies, causes a genetic disorder. This type of testing is offered to
individuals who have a family history of a genetic disorder and to people in certain
ethnic groups with an increased risk of specific genetic conditions. If both parents are
tested, the test can provide information about a couple's risk of having a child with a
genetic condition.

Prenatal testing
Prenatal testing is used to detect changes in a fetus's genes or chromosomes before
birth. This type of testing is offered during pregnancy if there is an increased risk that
the baby will have a genetic or chromosomal disorder. In some cases, prenatal testing
can lessen a couple's uncertainty or help them make decisions about a pregnancy. It
cannot identify all possible inherited disorders and birth defects, however.

Preimplantation testing
Preimplantation testing, also called preimplantation genetic diagnosis (PGD), is a
specialized technique that can reduce the risk of having a child with a particular genetic
or chromosomal disorder. It is used to detect genetic changes in embryos that were
created using assisted reproductive techniques (ART) such as in-vitro fertilization (IVF).
In-vitro fertilization involves removing egg cells from a woman’s ovaries and fertilizing
them with sperm cells outside the body. To perform preimplantation testing, a small
number of cells are taken from these embryos and tested for certain genetic changes.
Only embryos without these changes are implanted in the uterus to initiate a pregnancy.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 140

Predictive and presymptomatic testing
Predictive and presymptomatic types of testing are used to detect gene mutations
associated with disorders that appear after birth, often later in life. These tests can be
helpful to people who have a family member with a genetic disorder, but who have no
features of the disorder themselves at the time of testing. Predictive testing can identify
mutations that increase a person's risk of developing disorders with a genetic basis,
such as certain types of cancer. Presymptomatic testing can determine whether a
person will develop a genetic disorder, such as hereditary hemochromatosis (an iron
overload disorder), before any signs or symptoms appear. The results of predictive and
presymptomatic testing can provide information about a person’s risk of developing a
specific disorder and help with making decisions about medical care.

Forensic testing
Forensic testing uses DNA sequences to identify an individual for legal purposes. Unlike
the tests described above, forensic testing is not used to detect gene mutations
associated with disease. This type of testing can identify crime or catastrophe victims,
rule out or implicate a crime suspect, or establish biological relationships between
people (for example, paternity).

For more information about the uses of genetic testing:

Johns Hopkins Medicine provides additional information about genetic carrier screening
(https://www.hopkinsmedicine.org/gynecology_obstetrics/specialty_areas/fertility-center/
infertility-services/genetic-screening.html).

The Centre for Genetics Education offers an overview of prenatal testing (https://www.g
enetics.edu.au/SitePages/Prenatal-testing-overview.aspx), as well as fact sheets about
preimplantation genetic diagnosis (https://www.genetics.edu.au/SitePages/Preimplantati
on-genetic-diagnosis.aspx), screening tests during pregnancy, (https://www.genetics.ed
u.au/SitePages/Screening-tests-during-pregnancy.aspx) and diagnostic tests during
pregnancy (https://www.genetics.edu.au/SitePages/Diagnostic-tests-during-pregnancy.a
spx).

The University of Pennsylvania offers an explanation of preimplantation genetic

diagnosis (https://www.pennmedicine.org/for-patients-and-visitors/find-a-program-or-ser
vice/penn-fertility-care/embryo-screening).

Baby's First Test (https://www.babysfirsttest.org/newborn-screening/screening-101)

offers detailed information about newborn screening.

For information about forensic DNA testing, refer to a page about forensic DNA analysis
(https://learn.genetics.utah.edu/content/science/forensics/) from the Genetic Science
Learning Center at the University of Utah.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 141

 7.4 How is genetic testing done?
Once a person decides to proceed with genetic testing, a health care provider can
arrange testing. Genetic testing is often done as part of a genetic consultation.

Genetic tests are performed on a sample of blood, hair, skin, amniotic fluid (the fluid that
surrounds a fetus during pregnancy), or other tissue. For example, a procedure called a
buccal smear uses a small brush or cotton swab to collect a sample of cells from the
inside surface of the cheek. The sample is sent to a laboratory where technicians look
for specific changes in chromosomes, DNA, or proteins, depending on the suspected
disorder. The laboratory reports the test results in writing to a person's doctor or genetic
counselor, or directly to the patient if requested.

Newborn screening tests are done on a small blood sample, which is taken by pricking
the baby's heel. Unlike other types of genetic testing, a parent will usually only receive
the result if it is positive. If the test result is positive, additional testing is needed to
determine whether the baby has a genetic disorder.

Before a person has a genetic test, it is important to understand the testing procedure,
the benefits and limitations of the test, and the possible consequences of the test results.
The process of educating a person about the test and obtaining permission is called
informed consent.

Individuals interested in direct-to-consumer genetic testing do not need to go through a

health care provider to obtain a test, but they can get it directly from the testing
company. After undergoing direct-to-consumer genetic testing, people who test positive
for a condition or are found to be at higher risk of developing a disorder are encouraged
to follow-up with a genetic counselor or other health care provider.

For more information about genetic testing procedures:

A brief overview of how genetic testing is done (https://www.cancer.gov/about-cancer/ca
uses-prevention/genetics/genetic-testing-fact-sheet#how-is-genetic-testing-done) is also
available from The National Cancer Institute.

The Genetic Science Learning Center at the University of Utah provides an interactive
animation of DNA extraction techniques (https://learn.genetics.utah.edu/content/labs/ext
raction/).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 142

 7.5 What is informed consent?
Before a person has a genetic test, it is important to fully understand the testing
procedure, the benefits and limitations of the test, and the possible consequences of the
test results. The process of educating a person about the test and obtaining permission
to carry out testing is called informed consent. "Informed" means that the person has
enough information to make an educated decision about testing; "consent" refers to a
person's voluntary agreement to have the test done.

In general, informed consent can only be given by adults who are competent to make
medical decisions for themselves. For children and others who are unable to make their
own medical decisions (such as people with impaired mental status), informed consent
can be given by a parent, guardian, or other person legally responsible for making
decisions on that person's behalf.

Informed consent for genetic testing is generally obtained by a doctor or genetic

counselor during an office visit. The health care provider will discuss the test and
answer any questions. If the person wishes to have the test, he or she will then usually
read and sign a consent form.

Several factors are commonly included on an informed consent form:

• A general description of the test, including the purpose of the test and the condition
for which the testing is being performed.
• How the test will be carried out (for example, a blood sample).
• What the test results mean, including positive and negative results, and the
potential for uninformative results or incorrect results such as false positives or false
negatives.
• Any physical or emotional risks associated with the test.
• Whether the results can be used for research purposes.
• Whether the results might provide information about other family members' health,
including the risk of developing a particular condition or the possibility of having
affected children.
• How and to whom test results will be reported and under what circumstances
results can be disclosed (for example, to health insurance providers).
• What will happen to the test specimen after the test is complete.
• Acknowledgement that the person undergoing testing has had the opportunity to
discuss the test with a health care provider.
• The individual's signature, and possibly that of a witness.

The elements of informed consent may vary, because some states have laws that
specify factors that must be included. (For example, some states require disclosure that
the test specimen will be destroyed within a certain period of time after the test is
complete.)

Informed consent is not a contract, so a person can change their mind at any time after

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 143

giving initial consent. A person may choose not to go through with genetic testing even
after the test sample has been collected. A person simply needs to notify the health
care provider if the decision has been made to not continue with the testing process.

For more information about informed consent:

MedlinePlus offers general information about informed consent by adults (https://medlin
eplus.gov/ency/patientinstructions/000445.htm).

The National Cancer Institute discusses informed consent for genetic testing in the
context of inherited cancer syndromes (https://www.cancer.gov/about-cancer/causes-pr
evention/genetics/risk-assessment-pdq).

The National Human Genome Research Institute provides information about informed
consent in genomics research (https://www.genome.gov/about-genomics/policy-issues/I
nformed-Consent) and policies and legislation related to informed consent for genetic
research studies and testing (https://www.genome.gov/about-genomics/policy-issues/Inf
ormed-Consent/Required-Elements-of-Consent-Form).

The Centers for Disease Control and Prevention offers several examples of state-
required components of informed consent for genetic testing (https://www.cdc.gov/mmw
r/preview/mmwrhtml/rr5806a3.htm).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 144

 7.6 How can I be sure a genetic test is valid and useful?
Before undergoing genetic testing, it is important to be sure that the test is valid and
useful. A genetic test is valid if it provides an accurate result. Two main measures of
accuracy apply to genetic tests: analytical validity and clinical validity. Another measure
of the quality of a genetic test is its usefulness, or clinical utility.
• Analytical validity refers to how well the test predicts the presence or absence of a
particular gene or genetic change. In other words, can the test accurately detect
whether a specific genetic variant is present or absent?
• Clinical validity refers to how well the genetic variant being analyzed is related to
the presence, absence, or risk of a specific disease.
• Clinical utility refers to whether the test can provide helpful information about
diagnosis, treatment, management, or prevention of a disease.

All laboratories that perform health-related testing for disease prevention, diagnosis, or
treatment, including genetic testing, are subject to federal regulatory standards called
the Clinical Laboratory Improvement Amendments (CLIA) or even stricter state
requirements. CLIA standards cover how tests are performed, the qualifications of
laboratory personnel, and quality control and testing procedures for each laboratory. By
controlling the quality of laboratory practices, CLIA standards are designed to ensure
the analytical validity of genetic tests.

CLIA standards do not address the clinical validity or clinical utility of genetic tests. The
Food and Drug Administration (FDA) requires information about clinical validity for some
genetic tests, particularly those tests that can influence a person's medical care.
Additionally, states may require additional information on clinical validity for laboratory
tests performed for people living in that state. Test takers, health care providers, and
health insurance companies are often the ones who determine the clinical utility of a
genetic test.

It can be difficult to determine the quality of genetic tests sold directly to the public.
Some providers of direct-to-consumer genetic tests are not CLIA-certified, and many
direct-to-consumer genetic tests are not regulated by the FDA, so it can be difficult to
tell whether the tests are valid. If providers of direct-to-consumer genetic tests offer
easy-to-understand information about the scientific basis of their tests, it can help
people make more informed decisions. It may also be helpful to discuss any concerns
with a health care provider before ordering a direct-to-consumer genetic test and after
receiving test results.

For more information about determining the quality of genetic tests:

The Centers for Disease Control and Prevention (CDC) provides an explanation of the
factors used to evaluate genetic tests (https://www.cdc.gov/genomics/gtesting/ACCE/),
including analytical validity, clinical validity, and clinical utility, as part of their ACCE
project.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 145

The Genetic Alliance offers information about the quality of genetic tests and current
public policy issues (http://www.geneticalliance.org/advocacy/policyissues/genetictestin
g) surrounding their regulation.

The U.S. Centers for Medicare and Medicaid Services (CMS) provide an overview of
the Clinical Laboratory Improvement Amendments (CLIA) (https://www.cms.gov/Regulat
ions-and-Guidance/Legislation/CLIA/index) as well as information on their role in
regulating laboratory developed tests (https://www.cms.gov/Regulations-and-Guidance/
Legislation/CLIA/Downloads/LDT-and-CLIA_FAQs.pdf).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 146

 7.7 What do the results of genetic tests mean?
The results of genetic tests are not always straightforward, which often makes them
challenging to interpret and explain. Therefore, it is important for patients and their
families to ask questions about the potential meaning of genetic test results both before
and after the test is performed. When interpreting test results, health care providers
consider a person’s medical history, family history, and the type of genetic test that was
done.

A positive test result means that the laboratory found a change in a particular gene,
chromosome, or protein of interest. Depending on the purpose of the test, this result
may confirm a diagnosis, indicate that a person is a carrier of a particular genetic variant,
identify an increased risk of developing a disease (such as cancer), or suggest a need
for further testing. Because family members have some genetic material in common, a
positive test result may also have implications for certain blood relatives of the person
undergoing testing. It is important to note that a positive result of a predictive or
presymptomatic genetic test usually cannot establish the exact risk of developing a
disorder. Also, health care providers typically cannot use a positive test result to predict
the course or severity of a condition. Rarely, tests results can be false positive, which
occur when results indicate an increased risk for a genetic condition when the person is
unaffected.

A negative test result means that the laboratory did not find a change that is known to
affect health or development in the gene, chromosome, or protein under consideration.
This result can indicate that a person is not affected by a particular disorder, is not a
carrier of a specific genetic variant, or does not have an increased risk of developing a
certain disease. It is possible, however, that the test missed a disease-causing genetic
alteration because many tests cannot detect all genetic changes that can cause a
particular disorder. Further testing, or re-testing at a later date, may be required to
confirm a negative result. Rarely, tests results can be false negative, which occur when
the results indicate a decreased risk or a genetic condition when the person is actually
affected.

In some cases, a test result might not give any useful information. This type of result is
called uninformative, indeterminate, inconclusive, or ambiguous. Uninformative test
results sometimes occur because everyone has common, natural variations in their
DNA, called polymorphisms, that do not affect health. If a genetic test finds a change in
DNA that has not been confirmed to play a role in the development of disease, known
as a variant of uncertain significance (VUS or VOUS), it can be difficult to tell whether it
is a natural polymorphism or a disease-causing variant. For these variants, there may
not be enough scientific research to confirm or refute a disease association or the
research may be conflicting. An uninformative result cannot confirm or rule out a
specific diagnosis, and it cannot indicate whether a person has an increased risk of
developing a disorder. In some cases, testing other affected and unaffected family
members can help clarify this type of result.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 147

For more information about interpreting genetic test results:
The National Cancer Institute fact sheet Genetic Testing for Hereditary Cancer
Syndromes (https://www.cancer.gov/about-cancer/causes-prevention/genetics/genetic-t
esting-fact-sheet#q6) provides an explanation of positive and negative genetic test
results.

The Centers for Disease Control and Prevention (CDC) offers a fact sheet about genetic
testing (https://www.cdc.gov/genomics/gtesting/genetic_testing.htm), including an
explantion of the types of genetic test results.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 148

 7.8 What is the cost of genetic testing, and how long does it
take to get the results?
The cost of genetic testing can range from under $100 to more than $2,000, depending
on the nature and complexity of the test. The cost increases if more than one test is
necessary or if multiple family members must be tested to obtain a meaningful result.
For newborn screening, costs vary by state. Some states cover part of the total cost, but
most charge a fee of $30 to $150 per infant.

From the date that a sample is taken, it may take a few days to weeks to receive the
test results. Results for prenatal testing are usually available more quickly because time
is an important consideration in making decisions about a pregnancy. The doctor or
genetic counselor who orders a particular test can provide specific information about the
cost and time frame associated with that test.

For more information about the logistics of genetic testing:

The National Human Genome Research Institute discusses the coverage and
reimbursement of genetic tests (https://www.genome.gov/about-genomics/policy-issues/
Coverage-Reimbursement-of-Genetic-Tests).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 149

 7.9 Will health insurance cover the costs of genetic testing?
In many cases, health insurance plans will cover the costs of genetic testing when it is
recommended by a person's doctor. Health insurance providers have different policies
about which tests are covered, however. A person may wish to contact their insurance
company before testing to ask about coverage.

Some people may choose not to use their insurance to pay for testing. Instead, they
may opt to pay out-of-pocket for the test or pursue direct-to-consumer genetic testing, if
available. People considering genetic testing may want to find out more about their state'
s privacy protection laws before they ask their insurance company to cover the costs.
(Refer to What is genetic discrimination? for more information.)

For more information about insurance coverage of genetic testing:

The National Human Genome Research Institute provides information about Coverage
and Reimbursement of Genetic Tests (https://www.genome.gov/about-genomics/policy-i
ssues/Coverage-Reimbursement-of-Genetic-Tests).

Genes In Life discusses insurance coverage (http://www.genesinlife.org/after-diagnosis/

plan-future/insurance-and-financial-planning) and reimbursement (http://www.genesinlif
e.org/testing-services/testing-genetic-conditions/reimbursement-genetic-testing) for
genetic testing.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 150

 7.10 What are the benefits of genetic testing?
Genetic testing has potential benefits whether the results are positive or negative for a
gene mutation. Test results can provide a sense of relief from uncertainty and help
people make informed decisions about managing their health care. For example, a
negative result can eliminate the need for unnecessary checkups and screening tests in
some cases. A positive result can direct a person toward available prevention,
monitoring, and treatment options. Some test results can also help people make
decisions about having children. Newborn screening can identify genetic disorders early
in life so treatment can be started as early as possible.

For more information about the benefits of genetic testing:

The Centers for Disease Control and Prevention (CDC) offers a fact sheet about genetic
testing (https://www.cdc.gov/genomics/gtesting/genetic_testing.htm).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 151

 7.11 What are the risks and limitations of genetic testing?
The physical risks associated with most genetic tests are very small, particularly for
those tests that require only a blood sample or buccal smear (a method that samples
cells from the inside surface of the cheek). The procedures used for prenatal diagnostic
testing (called amniocentesis and chorionic villus sampling) carry a small but real risk of
losing the pregnancy (miscarriage) because they require a sample of amniotic fluid or
tissue from around the fetus.

Many of the risks associated with genetic testing involve the emotional, social, or
financial consequences of the test results. People may feel angry, depressed, anxious,
or guilty about their results. In some cases, genetic testing creates tension within a
family because the results can reveal information about other family members in
addition to the person who is tested. The possibility of genetic discrimination in
employment or insurance is also a concern. (Refer to What is genetic discrimination? for
additional information.)

Genetic testing can provide only limited information about an inherited condition. The
test often can't determine if a person will show symptoms of a disorder, how severe the
symptoms will be, or whether the disorder will progress over time. Another major
limitation is the lack of treatment strategies for many genetic disorders once they are
diagnosed.

A genetics professional can explain in detail the benefits, risks, and limitations of a
particular test. It is important that any person who is considering genetic testing
understand and weigh these factors before making a decision.

For more information about the risks and limitations of genetic testing:

The American College of Medical Genetics and Genomics (ACMG) published a policy
statement about the risks associated with incorrect genetic test results or interpretation (
https://www.acmg.net/docs/LDT_Release.pdf).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 152

 7.12 What is genetic discrimination?
Genetic discrimination occurs when people are treated differently by their employer or
insurance company because they have a gene mutation that causes or increases the
risk of an inherited disorder. Fear of discrimination is a common concern among people
considering genetic testing.

Several laws at the federal and state levels help protect people against genetic
discrimination. In particular, a federal law called the Genetic Information
Nondiscrimination Act (GINA) is designed to protect people from this form of
discrimination.

GINA has two parts: Title I, which prohibits genetic discrimination in health insurance,
and Title II, which prohibits genetic discrimination in employment. Title I makes it illegal
for health insurance providers to use or require genetic information to make decisions
about a person's insurance eligibility or coverage. This part of the law went into effect on
May 21, 2009. Title II makes it illegal for employers to use a person's genetic
information when making decisions about hiring, promotion, and several other terms of
employment. This part of the law went into effect on November 21, 2009.

GINA and other laws do not protect people from genetic discrimination in every
circumstance. For example, GINA does not apply when an employer has fewer than 15
employees. GINA also does not protect against genetic discrimination in forms of
insurance other than health insurance, such as life, disability, or long-term care
insurance.

For more information about genetic discrimination and GINA:

The National Human Genome Research Institute provides detailed discussions of
genetic discrimination and current laws that address this issue:
• Genetic Discrimination (https://www.genome.gov/about-genomics/policy-issues/Gen
etic-Discrimination)
• NHGRI Genome Statute and Legislation Database (https://www.genome.gov/about-
genomics/policy-issues/Genome-Statute-Legislation-Database)
• Genetic Information Nondiscrimination Act (GINA) of 2008 (https://www.genome.go
v/24519851/genetic-information-nondiscrimination-act-of-2008)

The Genetic Alliance offers links to resources and policy statements on genetic
discrimination (http://www.geneticalliance.org/advocacy/policyissues/geneticdiscriminati
on).

More detailed information about GINA is available from these resources

• Coalition for Genetic Fairness (http://www.geneticfairness.org/ginaresource.html)
• GINAHelp.org (http://www.ginahelp.org/)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 153

 7.13 Can genes be patented?
A gene patent is the exclusive rights to a specific sequence of DNA (a gene) given by a
government to the individual, organization, or corporation who claims to have first
identified the gene. Once granted a gene patent, the holder of the patent dictates how
the gene can be used, in both commercial settings, such as clinical genetic testing, and
in noncommercial settings, including research, for 20 years from the date of the patent.
Gene patents have often resulted in companies having sole ownership of genetic testing
for patented genes.

On June 13, 2013, in the case of the Association for Molecular Pathology v. Myriad
Genetics, Inc., the Supreme Court of the United States ruled that human genes cannot
be patented in the U.S. because DNA is a "product of nature." The Court decided that
because nothing new is created when discovering a gene, there is no intellectual
property to protect, so patents cannot be granted. Prior to this ruling, more than 4,300
human genes were patented. The Supreme Court's decision invalidated those gene
patents, making the genes accessible for research and for commercial genetic testing.

The Supreme Court's ruling did allow that DNA manipulated in a lab is eligible to be
patented because DNA sequences altered by humans are not found in nature. The
Court specifically mentioned the ability to patent a type of DNA known as
complementary DNA (cDNA). This synthetic DNA is produced from the molecule that
serves as the instructions for making proteins (called messenger RNA).

For more information about gene patenting and the Supreme Court
ruling:
Read about the Supreme Court case (https://www.scotusblog.com/case-files/cases/ass
ociation-for-molecular-pathology-v-myriad-genetics-inc/) and ruling against gene
patenting.

The National Institutes of Health (https://www.nih.gov/about-nih/who-we-are/nih-director

/statements/statement-nih-director-francis-collins-us-supreme-court-ruling-gene-patentin
g), the American College of Medical Genetics and Genomics (https://www.acmg.net/doc
s/GenePatientsDecision.pdf), and the American Medical Association (https://www.ama-
assn.org/delivering-care/precision-medicine/gene-patenting) voice their support for the
Supreme Court's ruling on gene patents.

The National Human Genome Research Institute discusses the relationship between
Intellectual Property and Genomics. (https://www.genome.gov/about-genomics/policy-is
sues/Intellectual-Property)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 154

 7.14 How are genetic screening tests different from genetic
diagnostic tests?
Screening tests evaluate an individual’s risk of developing a genetic condition, while
diagnostic tests identify genetic conditions. All genetic tests have both benefits and
limitations.

Genetic screening tests are generally used in people who do not have signs or
symptoms of a disorder. These tests estimate whether an individual’s risk of having a
certain condition is increased or decreased compared with the risk in other people in a
similar population. A positive result means that a person’s risk of developing the
condition is higher than average. A negative screening test means that a person’s risk is
lower than average. However, having a positive screening result does not mean the
individual has the condition. Because screening tests are only estimates, in some cases
the results indicate an increased risk for a genetic abnormality when the person is
actually unaffected (false positive), or the results indicate a decreased risk for a genetic
abnormality when the person is really affected (false negative). While genetic screening
tests do not provide a conclusive answer, they can help guide next steps, such as
whether additional, diagnostic testing is needed.

Genetic diagnostic tests are often used in people who have signs and symptoms. These
tests are used to confirm or rule out suspected genetic conditions. Diagnostic tests can
also help inform a person’s chance of developing a genetic condition or of passing on a
genetic condition to their children. Diagnostic testing can be performed before birth or at
any time during a person's life, but it is not available for all genes or all genetic
conditions. The results of a diagnostic test can be used to guide a person's choices
about health care and the management of the disorder.

Examples of genetic screening tests include:

Noninvasive prenatal testing/screening (NIPT/NIPS): This screening test is performed

before birth to help determine the risk that a fetus will be born with certain genetic
abnormalities, such as Down syndrome and other chromosomal disorders.

Newborn screening: In the United States, a screening test is performed on all newborns
shortly after birth. This test can assess the risk for developing more than 35 genetic
conditions. For many of these conditions, the test analyzes various protein and enzyme
levels, which would be abnormal in affected individuals.

Examples of genetic diagnostic tests include:

Molecular gene tests: These tests determine the order of DNA building blocks
(nucleotides) in an individual's genetic code, a process called DNA sequencing. The
purpose of these tests is to identify genetic changes that can cause disease.

Chromosomal tests: These tests analyze whole chromosomes or long lengths of DNA to
identify large-scale changes, such as an extra or missing copy of a chromosome
(trisomy or monosomy, respectively) or abnormalities of large segments of

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 155

chromosomes, that underlie certain genetic conditions.

For more information about the difference between screening and

diagnostic genetic tests:
The Centers for Disease Control and Prevention (CDC) provides information about
genetic testing (https://www.cdc.gov/genomics/gtesting/genetic_testing.htm).

The American Medical Association provides details on genetic testing (https://www.ama

-assn.org/delivering-care/precision-medicine/genetic-testing).

Genes In Life discusses diagnostic genetic testing (http://www.genesinlife.org/testing-se

rvices/testing-genetic-conditions/diagnostic-testing).

MedlinePlus has additional information on newborn screening (https://medlineplus.gov/n

ewbornscreening.html).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 156

 7.15 How does genetic testing in a research setting differ
from clinical genetic testing?
The main differences between clinical genetic testing and research testing are the
purpose of the test and who receives the results. The goals of research testing include
finding unknown genes, learning how genes work, developing tests for future clinical
use, and advancing our understanding of genetic conditions. The results of testing done
as part of a research study are usually not available to patients or their healthcare
providers. Clinical testing, on the other hand, is done to find out about an inherited
disorder in an individual patient or family. People receive the results of a clinical test and
can use them to help them make decisions about medical care or reproductive issues.

It is important for people considering genetic testing to know whether the test is
available on a clinical or research basis. Clinical and research testing both involve a
process of informed consent in which patients learn about the testing procedure, the
risks and benefits of the test, and the potential consequences of testing.

For more information about the differences between clinical and

research testing:
The Ohio State University’s Wexner Medical Center describes the difference between
clinical and research genetic testing (https://wexnermedical.osu.edu/genetics/facts-abou
t-testing).

Additional information about clinical and research tests (https://www.ncbi.nlm.nih.gov/gtr

/docs/about/#tests) is available from the Genetic Testing Registry.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 157

 7.16 What are whole exome sequencing and whole genome
sequencing?
Determining the order of DNA building blocks (nucleotides) in an individual's genetic
code, called DNA sequencing, has advanced the study of genetics and is one technique
used to test for genetic disorders. Two methods, whole exome sequencing and whole
genome sequencing, are increasingly used in healthcare and research to identify
genetic variations; both methods rely on new technologies that allow rapid sequencing
of large amounts of DNA. These approaches are known as next-generation sequencing
(or next-gen sequencing).

The original sequencing technology, called Sanger sequencing (named after the
scientist who developed it, Frederick Sanger), was a breakthrough that helped scientists
determine the human genetic code, but it is time-consuming and expensive. The Sanger
method has been automated to make it faster and is still used in laboratories today to
sequence short pieces of DNA, but it would take years to sequence all of a person's
DNA (known as the person's genome). Next-generation sequencing has sped up the
process (taking only days to weeks to sequence a human genome) while reducing the
cost.

With next-generation sequencing, it is now feasible to sequence large amounts of DNA,

for instance all the pieces of an individual's DNA that provide instructions for making
proteins. These pieces, called exons, are thought to make up 1 percent of a person's
genome. Together, all the exons in a genome are known as the exome, and the method
of sequencing them is known as whole exome sequencing. This method allows
variations in the protein-coding region of any gene to be identified, rather than in only a
select few genes. Because most known mutations that cause disease occur in exons,
whole exome sequencing is thought to be an efficient method to identify possible
disease-causing mutations.

However, researchers have found that DNA variations outside the exons can affect
gene activity and protein production and lead to genetic disorders--variations that whole
exome sequencing would miss. Another method, called whole genome sequencing,
determines the order of all the nucleotides in an individual's DNA and can determine
variations in any part of the genome.

While many more genetic changes can be identified with whole exome and whole
genome sequencing than with select gene sequencing, the significance of much of this
information is unknown. Because not all genetic changes affect health, it is difficult to
know whether identified variants are involved in the condition of interest. Sometimes, an
identified variant is associated with a different genetic disorder that has not yet been
diagnosed (these are called incidental or secondary findings).

In addition to being used in the clinic, whole exome and whole genome sequencing are
valuable methods for researchers. Continued study of exome and genome sequences
can help determine whether new genetic variations are associated with health
conditions, which will aid disease diagnosis in the future.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 158

For more information about DNA sequencing technologies and their use:
An illustration of the decline in the cost of DNA sequencing (https://www.genome.gov/ab
out-genomics/fact-sheets/Sequencing-Human-Genome-cost), including that caused by
the introduction of new technologies, is provided by the National Human Genome
Research Institute.

The American College of Medical Genetics and Genomics has laid out their policies
regarding whole exome and whole genome sequencing (https://www.acmg.net/PDFLibr
ary/Genomic-Sequencing-Clinical-Application.pdf), including when these methods
should be used, what results may arise, and what the results might indicate.

GeneReviews compares whole genome sequencing, whole exome sequencing, and the
sequencing of a selection of individual genes (https://www.ncbi.nlm.nih.gov/books/NBK2
79899/), particularly their use in the diagnosis of genetic conditions.

The Mount Sinai School of Medicine Genomics Core Facility describes the techniques
used in whole exome sequencing (https://icahn.mssm.edu/research/genomics/core-facili
ty/whole-exome).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 159

 7.17 What are secondary findings from genetic testing?
Secondary findings are genetic test results that provide information about changes
(variants) in a gene unrelated to the primary purpose for the testing.

When a clinician orders a genetic test to discover the genetic cause of a particular
condition, the test will often sequence one or a few genes that seem most likely to be
associated with that individual’s set of signs and symptoms. However, if the individual’s
signs and symptoms do not have an obvious genetic cause, a clinician might order a
test that sequences all of the pieces of an individual's DNA that provide instructions for
making proteins (called an exome) or a test that sequences all of an individual’s DNA
building blocks (nucleotides), called a genome. These tests are called whole exome
sequencing and whole genome sequencing, respectively.

Many more genetic changes can be identified with whole exome and whole genome
sequencing than by sequencing just one or a few genes. Sometimes, testing finds a
variant that is associated with a condition other than the one for which testing was
originally indicated. This is called a secondary finding. Some individuals with a
secondary finding may not yet have any of the symptoms associated with the condition,
but may be at risk of developing it later in life. For example, a person with a variant in
the BRCA1gene, which is associated with an increased risk of breast cancer and
ovarian cancer, may not have developed cancer. Other individuals with secondary
findings may have a known medical condition, such as extremely high cholesterol, but
receive results that indicate a genetic cause for that condition, such as a variant in the
LDLR gene.

In 2013, then again in 2017 and 2021, the American College of Medical Genetics and
Genomics (ACMG) recommended that all labs performing whole exome and whole
genome sequencing tests report particular secondary findings, in addition to any
variants that are found related to the primary purpose of the testing. In the 2021
updated recommendations, ACMG proposed a list of 73 genes that are associated with
a variety of conditions, from cancer to heart disease. The 73 genes for which secondary
findings are reported were chosen because they are associated with conditions that
have a definable set of clinical features, the possibility of early diagnosis, a reliable
clinical genetic test, and effective intervention or treatment. The goal of reporting these
secondary findings to an individual is to provide medical benefit by preventing or better
managing health conditions. The variants that are reported are known to cause disease.
Variants of unknown significance, whose involvement in disease at the current time is
unclear, are not reported.

The information provided by secondary findings can be very important because it may
help prevent a disease from occurring or guide the management of signs and symptoms
if the disease develops or is already present. However, as with any type of medical
diagnosis, the news of an unexpected potential health problem may lead to additional
health costs and stress for individuals and their families. On the basis of secondary
findings, additional testing to confirm results, ongoing screening tests, or preventive
care may be advised. Individuals receiving whole exome or whole genome sequencing
can choose to “opt out” of analysis of the 73 secondary finding genes and not receive

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 160

variant results. As whole exome and whole genome sequencing become more common, it
is important for individuals to understand what type of information they may learn and
how it can impact their medical care.

Scientific journal articles for further reading

Robert C. Green MD, MPH, Jonathan S. Berg MD, PhD, Wayne W. Grody MD, PhD,
Sarah S. Kalia ScM, CGC, Bruce R. Korf MD, PhD, Christa L. Martin PhD, FACMG,
Amy L. McGuire JD, PhD, Robert L. Nussbaum MD, Julianne M. O’Daniel MS, CGC,
Kelly E. Ormond MS, CGC, Heidi L. Rehm PhD, FACMG, Michael S. Watson PhD,
FACMG, Marc S. Williams MD, FACMG & Leslie G. Biesecker MD. ACMG
recommendations for reporting of incidental findings in clinical exome and genome
sequencing. Genet Med. 2013 Jul;15(7):565-74. doi: 10.1038/gim.2013.73. Epub 2013
Jun 20. PubMed: 23788249. Free full-text article from PubMed Central: 3727274.

Sarah S. Kalia ScM, Kathy Adelman, Sherri J. Bale PhD, Wendy K. Chung MD, PhD,
Christine Eng MD, James P. Evans MD, PhD, Gail E. Herman MD, PhD, Sophia B.
Hufnagel MD, Teri E. Klein PhD, Bruce R. Korf MD, PhD, Kent D. McKelvey MD, Kelly E.
Ormond MS, C. Sue Richards PhD, Christopher N. Vlangos PhD, Michael Watson PhD,
Christa L. Martin PhD & David T. Miller MD, PhD ; on behalf of the ACMG
Secondary Findings Maintenance Working Group. Recommendations for reporting of
secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF
v2.0): a policy statement of the American College of Medical Genetics and Genomics.
Genet Med. 2017 Feb;19(2):249-255. doi: 10.1038/gim.2016.190. Epub 2016 Nov 17.
PubMed: 27854360.

Miller DT, Lee K, Chung WK, Gordon AS, Herman GE, Klein TE, Stewart DR, Amendola
LM, Adelman K, Bale SJ, Gollob MH, Harrison SM, Hershberger RE, McKelvey K,
Richards CS, Vlangos CN, Watson MS, Martin CL; ACMG Secondary Findings Working
Group. ACMG SF v3.0 list for reporting of secondary findings in clinical exome and
genome sequencing: a policy statement of the American College of Medical Genetics
and Genomics (ACMG). Genet Med. 2021 May 20. doi: 10.1038/s41436-021-01172-3.
Epub ahead of print. PMID: 34012068.

Learn more about secondary genetic findings:

The Columbia University Medical Center has videos giving an Introduction to Secondary
Findings (http://www.learninggenetics.org/secondary-findings.html) as well as
discussing the Pros and Cons of Secondary Findings (http://www.learninggenetics.org/p
ros-cons.html) and Decisions about Secondary Findings (http://www.learninggenetics.or
g/decisions.html).

The American College of Medical Genetics and Genomics provides ACT Sheets (https:/
/www.ncbi.nlm.nih.gov/books/NBK553548/) on secondary findings for mutliple genes,
which is available through the NCBI Bookshelf.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 161

MedlinePlus Genetics has information on many of the genetic conditions (https://vsearc
h.nlm.nih.gov/vivisimo/cgi-bin/query-meta?&v:project=medlineplus&v:sources
=medlineplus-bundle&query=secondary%20findings&binning-state=group%3
d%3dGenetics%0aalpha%3d%3dGenetic%20Conditions&) and genes (https://vse
arch.nlm.nih.gov/vivisimo/cgi-bin/query-meta?&v:project=medlineplus&v:sourc
es=medlineplus-bundle&query=secondary%20findings&binning-state=group%
3d%3dGenetics%0aalpha%3d%3dGenes&)that are associated with the 73 ACMG-
recommended secondary finding genes.

The U.S. National Library of Medicine provides a list of the ACMG-recommended

secondary finding genes and their associated conditions (https://www.ncbi.nlm.nih.gov/c
linvar/docs/acmg/).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 162

 7.18 What is noninvasive prenatal testing (NIPT) and what
disorders can it screen for?
Noninvasive prenatal testing (NIPT), sometimes called noninvasive prenatal screening
(NIPS), is a method of determining the risk that the fetus will be born with certain
genetic abnormalities. This testing analyzes small fragments of DNA that are circulating
in a pregnant woman’s blood. Unlike most DNA, which is found inside a cell’s nucleus,
these fragments are free-floating and not within cells, and so are called cell-free DNA
(cfDNA). These small fragments usually contain fewer than 200 DNA building blocks
(base pairs) and arise when cells die off and get broken down and their contents,
including DNA, are released into the bloodstream.

During pregnancy, the mother’s bloodstream contains a mix of cfDNA that comes from
her cells and cells from the placenta. The placenta is tissue in the uterus that links the
fetus and the mother’s blood supply. These cells are shed into the mother’s
bloodstream throughout pregnancy. The DNA in placental cells is usually identical to the
DNA of the fetus. Analyzing cfDNA from the placenta provides an opportunity for early
detection of certain genetic abnormalities without harming the fetus.

NIPT is most often used to look for chromosomal disorders that are caused by the
presence of an extra or missing copy (aneuploidy) of a chromosome. NIPT primarily
looks for Down syndrome (trisomy 21, caused by an extra chromosome 21), trisomy 18
(caused by an extra chromosome 18), trisomy 13 (caused by an extra chromosome 13),
and extra or missing copies of the X chromosome and Y chromosome (the sex
chromosomes). The accuracy of the test varies by disorder.

NIPT may include screening for additional chromosomal disorders that are caused by
missing (deleted) or copied (duplicated) sections of a chromosome. NIPT is beginning
to be used to test for genetic disorders that are caused by changes (variants) in single
genes. As technology improves and the cost of genetic testing decreases, researchers
expect that NIPT will become available for many more genetic conditions.

NIPT is considered noninvasive because it requires drawing blood only from the
pregnant woman and does not pose any risk to the fetus. NIPT is a screening test,
which means that it will not give a definitive answer about whether or not a fetus has a
genetic condition. The test can only estimate whether the risk of having certain
conditions is increased or decreased. In some cases, NIPT results indicate an
increased risk for a genetic abnormality when the fetus is actually unaffected (false
positive), or the results indicate a decreased risk for a genetic abnormality when the
fetus is actually affected (false negative). Because NIPT analyzes both fetal and
maternal cfDNA, the test may detect a genetic condition in the mother.

There must be enough fetal cfDNA in the mother’s bloodstream to be able to identify
fetal chromosome abnormalities. The proportion of cfDNA in maternal blood that comes
from the placenta is known as the fetal fraction. Generally, the fetal fraction must be
above 4 percent, which typically occurs around the tenth week of pregnancy. Low fetal
fractions can lead to an inability to perform the test or a false negative result. Reasons
for low fetal fractions include testing too early in the pregnancy, sampling errors,

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 163

maternal obesity, and fetal abnormality.

There are multiple NIPT methods to analyze fetal cfDNA. To determine chromosomal
aneuploidy, the most common method is to count all cfDNA fragments (both fetal and
maternal). If the percentage of cfDNA fragments from each chromosome is as expected,
then the fetus has a decreased risk of having a chromosomal condition (negative test
result). If the percentage of cfDNA fragments from a particular chromosome is more
than expected, then the fetus has an increased likelihood of having a trisomy condition
(positive test result). A positive screening result indicates that further testing (called
diagnostic testing, because it is used to diagnose a disease) should be performed to
confirm the result.

Scientific journal articles for further reading

Committee Opinion No. 640: Cell-Free DNA Screening For Fetal Aneuploidy. Obstet
Gynecol. 2015 Sep;126(3):e31-7. doi: 10.1097/AOG.0000000000001051. PubMed:
26287791.

Dondorp W, de Wert G, Bombard Y, Bianchi DW, Bergmann C, Borry P, Chitty LS,

Fellmann F, Forzano F, Hall A, Henneman L, Howard HC, Lucassen A, Ormond K,
Peterlin B, Radojkovic D, Rogowski W, Soller M, Tibben A, Tranebjærg L, van El CG,
Cornel MC. Non-invasive prenatal testing for aneuploidy and beyond: challenges of
responsible innovation in prenatal screening. Summary and recommendations. Eur J
Hum Genet. 2015 Apr 1. doi: 10.1038/ejhg.2015.56. [Epub ahead of print] PubMed:
25828867.

Goldwaser T, Klugman S. Cell-free DNA for the detection of fetal aneuploidy. Fertil
Steril. 2018 Feb;109(2):195-200. doi: 10.1016/j.fertnstert.2017.12.019. PubMed:
29447662.

Gregg AR, Skotko BG, Benkendorf JL, Monaghan KG, Bajaj K, Best RG, Klugman S,
Watson MS. Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a
position statement of the American College of Medical Genetics and Genomics. Genet
Med. 2016 Oct;18(10):1056-65. doi: 10.1038/gim.2016.97. Epub 2016 Jul 28. PubMed:
27467454.Rose NC, Kaimal AJ, Dugoff L, Norton ME; American College of
Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics;
Committee on Genetics; Society for Maternal-Fetal Medicine. Screening for Fetal
Chromosomal Abnormalities: ACOG Practice Bulletin, Number 226. Obstet Gynecol.
2020 Oct;136(4):e48-e69. doi: 10.1097/AOG.0000000000004084. PubMed: 32804883.
Skrzypek H, Hui L. Noninvasive prenatal testing for fetal aneuploidy and single gene
disorders. Best Pract Res Clin Obstet Gynaecol. 2017 Jul;42:26-38. doi: 10.1016/j.
bpobgyn.2017.02.007. Epub 2017 Feb 28. PubMed: 28342726.

For more information about NIPT:

MedlinePlus Medical Test: Prenatal Cell-Free DNA Screening (https://medlineplus.gov/l
ab-tests/prenatal-cell-free-dna-screening/)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 164

Genomics Education Programme (UK): What is NIPT? (https://www.genomicseducation
.hee.nhs.uk/blog/what-is-nipt/)

National Human Genome Research Institute: Noninvasive Prenatal Genetic Testing (htt
ps://www.genome.gov/dna-day/15-ways/noninvasive-prenatal-genetic-testing)

Centre for Genetics Education (Australia): Fact Sheet: Non-Invasive Prenatal Testing
(NIPT) (https://www.genetics.edu.au/SitePages/Non-invasive-prenatal-testing.aspx)

National Society of Genetic Counselors: Questions Expectant Mothers Should Ask

Before Prenatal Screening (https://www.aboutgeneticcounselors.org/Resources-to-Help
-You/Post/questions-expectant-mothers-should-ask-before-prenatal-screening)

Eunice Kennedy Shriver National Institute of Child Health and Human Development:
How do Health Care Providers Diagnose Birth Defects? (https://www.nichd.nih.gov/healt
h/topics/birthdefects/conditioninfo/diagnosed)

Genetic Support Foundation: Prenatal Cell-free DNA (cfDNA) Screening (https://www.g

eneticsupport.org/genetics-pregnancy/prenatal-screening-tests/cell-free-dna-screening/)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 165

 7.19 What is circulating tumor DNA and how is it used to
diagnose and manage cancer?
Circulating tumor DNA (ctDNA) is found in the bloodstream and refers to DNA that
comes from cancerous cells and tumors. Most DNA is inside a cell’s nucleus. As a
tumor grows, cells die and are replaced by new ones. The dead cells get broken down
and their contents, including DNA, are released into the bloodstream. ctDNA are small
pieces of DNA, usually comprising fewer than 200 building blocks (nucleotides) in length.

The quantity of ctDNA varies among individuals and depends on the type of tumor, its
location, and for cancerous tumors, the cancer stage.

Detection of ctDNA can be helpful in the following cases:

• Detecting and diagnosing a tumor. Because tumor DNA has acquired multiple
genetic changes (variants), leading to tumor development, ctDNA is not an exact
match to the individual’s DNA. Finding DNA with genetic differences aids in tumor
detection. Diagnosing the type of tumor using ctDNA can reduce the need for getting
a sample of the tumor tissue (tumor biopsy), which can be challenging when a tumor
is difficult to access, such as a tumor in the brain or lung.
• Guiding tumor-specific treatment. Analyzing the genome of tumor cells using ctDNA
can help doctors determine which treatment will be most effective. Currently,
however, approval from the U.S. Food and Drug Administration for ctDNA testing to
personalize cancer treatment is limited.
• Monitoring treatment. A decrease in the quantity of ctDNA suggests the tumor is
shrinking and treatment is successful.
• Monitoring periods with no symptoms (remission of cancer). A lack of ctDNA in the
bloodstream indicates that the cancer has not returned.

Scientists have discovered that dying tumor cells release small pieces of their DNA into
the bloodstream. These pieces are called cell-free circulating tumor DNA (ctDNA).
(Figure 7.2)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 166

 FIGURE 7.2: Illustration of DNA fragments in a blood vessel with arrows
indicating the fragments originated from tumors in body organs.

Scientific journal articles for further reading

Merker JD, Oxnard GR, Compton C, Diehn M, Hurley P, Lazar AJ, Lindeman N,
Lockwood CM, Rai AJ, Schilsky RL, Tsimberidou AM, Vasalos P, Billman BL, Oliver TK,
Bruinooge SS, Hayes DF, Turner NC. Circulating Tumor DNA Analysis in Patients With
Cancer: American Society of Clinical Oncology and College of American Pathologists
Joint Review. J Clin Oncol. 2018 Jun 1;36(16):1631-1641. doi: 10.1200/JCO.2017.76.
8671. Epub 2018 Mar 5. PubMed: 29504847.

Stewart CM, Kothari PD, Mouliere F, Mair R, Somnay S, Benayed R, Zehir A, Weigelt B,
Dawson SJ, Arcila ME, Berger MF, Tsui DW. The value of cell-free DNA for molecular
pathology. J Pathol. 2018 Apr;244(5):616-627. doi: 10.1002/path.5048. Epub 2018 Mar
12. PubMed: 29380875.

For more information about ctDNA:

National Human Genome Research Institute: Cancer Genomics (https://www.genome.g
ov/dna-day/15-ways/cancer-genomics)

PHG Foundation (UK): Circulating Tumour DNA Technology: The Future of Cancer

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 167

Management? (https://www.phgfoundation.org/briefing/ctDNA-the-future-of-cancer-managem
ent)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 168

 8
Direct-to-Consumer Genetic Testing
8.1 What is direct-to-consumer genetic testing?
Most of the time, genetic testing is done through healthcare providers such as
physicians, nurse practitioners, or genetic counselors. Healthcare providers determine
which test is needed, order the test from a laboratory, collect the DNA sample, send the
DNA sample to the lab for testing and interpretation, and share the results with the
patient. Often, a health insurance company covers part or all of the cost of testing. This
type of testing is known as clinical genetic testing.

Direct-to-consumer genetic testing is different: these genetic tests are marketed directly
to customers via television, radio, print advertisements, or the Internet, and the tests
can be bought online or in stores. After purchasing a test kit, customers send the
company a DNA sample and receive their results directly from a secure website or app
or in a written report. Direct-to-consumer genetic testing provides people access to their
genetic information without necessarily involving a healthcare provider or health
insurance company in the process.

Many companies currently offer direct-to-consumer genetic tests for a variety of

purposes. The most popular tests use a limited set of genetic variations to make
predictions about a certain aspects of health, provide information about common traits,
and offer clues about a person’s ancestry. The number of companies providing direct-to-
consumer genetic testing is growing, along with the range of health information provided
by these tests. Because there is currently little regulation of direct-to-consumer genetic
testing services, it is important to assess the quality of available services before
pursuing any testing.

Other names for direct-to-consumer genetic testing include DTC genetic testing, direct-
access genetic testing, at-home genetic testing, and home DNA testing. Ancestry
testing (also called genealogy testing) is also considered a form of direct-to-consumer
genetic testing.

For more information about direct-to-consumer genetic testing:

Centers for Disease Control and Prevention (CDC) Genomics and Health Impact Blog:
Direct to Consumer Genetic Testing: Think Before You Spit, 2017 Edition! (https://blogs.
cdc.gov/genomics/2017/04/18/direct-to-consumer-2/)

National Human Genome Research Institute: Direct-to-Consumer Genomic Testing (htt

ps://www.genome.gov/dna-day/15-ways/direct-to-consumer-genomic-testing)

National Society of Genetic Counselors: What is At-Home Genetic Testing? (https://ww

w.aboutgeneticcounselors.org/Reasons-to-See-a-Genetic-Counselor/At-Home-Genetic-
Testing)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 169

American Medical Association: Direct-to-Consumer Genetic Testing (https://www.ama-a
ssn.org/delivering-care/precision-medicine/direct-consumer-genetic-testing)

The Federal Trade Commission: Direct to Consumer Genetic Tests (https://www.consu

mer.ftc.gov/articles/0166-direct-consumer-genetic-tests)

Genes in Life: Direct-to-Consumer Genetic Testing (http://www.genesinlife.org/testing-s

ervices/testing-genetic-conditions/direct-consumer-genetic-testing)

Johns Hopkins Medicine: Five Things to Know about Direct-to-Consumer Genetic Tests
(https://www.hopkinsmedicine.org/news/articles/five-things-to-know-about-direct-to-cons
umer-genetic-tests)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 170

 8.2 What kinds of direct-to-consumer genetic tests are
available?
With direct-to-consumer genetic testing companies offering a variety of tests, it can be
challenging to determine which tests will be most informative and helpful to you. When
considering testing, think about what you hope to get out of the test. Some direct-to-
consumer genetic tests are very specific (such as paternity tests), while other services
provide a broad range of health, ancestry, and lifestyle information.

Major types of direct-to-consumer genetic tests include:

Disease risk and health

The results of these tests estimate your genetic risk of developing several common
diseases that are caused by environmental factors and multiple variants in several
genes. These common diseases include such as celiac disease, Parkinson's disease,
and Alzheimer's disease. Some companies also include a person’s carrier status for
less common conditions, including cystic fibrosis and sickle cell disease. A carrier is
someone who has a gene variant in one copy of the gene that, when present in both
copies of the gene, causes a genetic disorder. The tests may also look for certain
genetic variations that could be related to other health-related traits, such as weight and
metabolism (how a person’s body converts the nutrients from food into energy). These
tests may also provide information about how a person may respond to certain drugs
(pharmacogenomics).

Ancestry or genealogy
The results of these tests provide clues about where a person's ancestors might have
come from, their ethnicity, and genetic connections between families. For more
information, see What is genetic ancestry testing?

Kinship
The results of these tests can indicate whether tested individuals are biologically related
to one another. For example, kinship testing can establish whether one person is the
biological father of another (paternity testing).

Lifestyle
The results of these tests claim to provide information about lifestyle factors, such as
nutrition, fitness, weight loss, skincare, sleep, and even your wine preferences, based
on variations in your DNA. Many of the companies that offer this kind of testing also sell
services, products, or programs that they customize on the basis of your test results.

Before choosing a direct-to-consumer genetic test, find out what kinds of health,
ancestry, or other information will be reported to you. Most direct-to-consumer genetic

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 171

tests do not sequence whole genes, but look at only a subset of variants within the genes
associated with the conditions or traits they report on. For more comprehensive genetic
testing, see a genetics professional. Think about whether there is any information you
would rather not know. In some cases, you can decline to find out specific information if
you tell the company before it delivers your results.

Learn more about the available types of direct-to-consumer genetic

testing:
National Society of Genetic Counselors: What is At-Home Genetic Testing? (https://ww
w.aboutgeneticcounselors.org/Reasons-to-See-a-Genetic-Counselor/At-Home-Genetic-
Testing)

GeneReviews: Resources for Genetics Professionals--Direct-to-Consumer Genetic

Testing (https://www.ncbi.nlm.nih.gov/books/NBK542335/)

Applied & Translational Genomics (free full-text via PubMed Central): Only a click
away — DTC genetics for ancestry, health, love…and more: A view of the business and
regulatory landscape (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4796702/)

Stanford at the Tech: Kinship Testing (https://genetics.thetech.org/ask-a-geneticist/best-

half-sibling-dna-test)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 172

 8.3 What is genetic ancestry testing?
Genetic ancestry testing, or genetic genealogy, is a way for people interested in family
history (genealogy) to go beyond what they can learn from relatives or from historical
documentation. Examination of DNA variations can provide clues about where a person'
s ancestors might have come from and about relationships between families. Certain
patterns of genetic variation are often shared among people of particular backgrounds.
The more closely related two individuals, families, or populations are, the more patterns
of variation they typically share.

Three types of genetic ancestry testing are commonly used for genealogy:

Y chromosome testing
Variations in the Y chromosome can be used to explore ancestry in the direct male line.
Only individuals with a Y chromosome (typically males) can have this type of testing
done. However, people interested in this type of genetic testing sometimes recruit a
relative to have the test done. Because the Y chromosome is passed on in the same
pattern as are family names (surnames) in many cultures, Y chromosome testing is
often used to investigate questions such as whether two families with the same
surname are related.

Mitochondrial DNA testing

This type of testing identifies genetic variations in mitochondrial DNA. Although most
DNA is packaged in chromosomes within the cell nucleus, cell structures called
mitochondria also have a small amount of their own DNA (known as mitochondrial DNA).
Both males and females have mitochondrial DNA so this type of testing can be used by
either sex. Mitochondria DNA is passed on solely from egg cells so it provides
information about the direct female ancestral line. Mitochondrial DNA testing can be
useful for genealogy because it preserves information about female ancestors that may
be lost from the historical record because of the way surnames are often passed down.

Single nucleotide polymorphism testing

These tests evaluate large numbers of individual variations (single nucleotide
polymorphisms or SNPs) across a person’s entire genome. The results are compared to
similar SNPs in a testing database to provide an estimate of a person's ethnic
background. For example, the pattern of SNPs might indicate that a person's ancestry is
approximately 50 percent African, 25 percent European, 20 percent Asian, and 5
percent unknown. (Sometimes, more regional specificity can be provided.) Genealogists
use this type of test because Y chromosome and mitochondrial DNA test results, which
represent only single ancestral lines, do not capture the overall ancestral background of
an individual.

Genetic ancestry testing has a number of limitations. Test providers compare individuals'
test results to different databases of SNPs, so ethnicity estimates may not be

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 173

consistent from one provider to another. Additionally, these databases do not have equal
coverage of SNPs for all ethnic populations; so results for minority populations may be
nonspecific or inaccurate. Also, because most human populations have migrated many
times throughout their history and mixed with nearby groups, ethnicity estimates based
on genetic testing may differ from an individual's expectations. In ethnic groups with a
smaller range of genetic variation due to the group's size and history, most members
share many SNPs, and it may be difficult to distinguish people who have a relatively
recent common ancestor, such as fourth cousins, from the group as a whole.

Genetic ancestry testing is offered by several companies and organizations. Most

companies provide online forums and other services to allow people who have been
tested to share and discuss their results with others, which may allow them to discover
previously unknown relationships. On a larger scale, combined genetic ancestry test
results from many people can be used by scientists to explore the history of populations
as they arose, migrated, and mixed with other groups.

For more information about genetic ancestry testing:

The University of Utah provides video tutorials (https://learn.genetics.utah.edu/content/b
asics/molgen/) on molecular genealogy.

The International Society of Genetic Genealogy (https://isogg.org/) promotes the use of

DNA testing in genealogy.

The National Human Genome Research Institute discusses human origins and ancestry
(https://www.genome.gov/dna-day/15-ways/human-origins-ancestry).

The Tech Museum of Innovation provides information about how ancestry testing works
(https://genetics.thetech.org/ask-a-geneticist/how-ancestry-tests-work).

The Smithsonian National Museum of Natural History's exhibit 'Genome: Unlocking Life'
s Code' discusses the difference between ancestry and race (https://www.unlockinglifes
code.org/genomics-insights/ancestry-vs-race-implications-society). The exhibit also
discusses the Great Human Migration (https://www.unlockinglifescode.org/genomics-ins
ights/hominid-development-great-human-migration-and-concept-race) and its influence
on heredity and genealogy.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 174

 8.4 What are the benefits and risks of direct-to-consumer
genetic testing?
Direct-to-consumer genetic testing has both benefits and limitations, as they are
somewhat different than those of genetic testing ordered by a healthcare provider.

Benefits
• Direct-to-consumer genetic testing promotes awareness of genetic diseases.
• It provides personalized information about your health, disease risk, and other traits.
• It may help you be more proactive about your health.
• It does not require approval from a healthcare provider or health insurance
company.
• As results are provided directly to the individual, they are not in your insurance or
medical record (unless you share results with your healthcare professional).
• It is often less expensive than genetic testing obtained through a healthcare
provider, which can make testing more accessible to people with no or limited health
insurance.
• DNA sample collection is usually simple and noninvasive, and results are available
quickly.
• Your anonymous data is added to a large database that can be used to further
medical research. Depending on the company, the database may represent up to
several million participants.

Risks and limitations

• Tests may not be available for the health conditions or traits that interest you.
• This type of testing cannot tell definitively whether you will or will not get a particular
disease. Results often need to be confirmed with genetic tests administered by a
healthcare professional.
• The tests look only at a subset of variants within genes, so disease-causing variants
can be missed.
• Unexpected information that you receive about your health, family relationships, or
ancestry may be stressful or upsetting.
• As testing is done outside of a healthcare clinic, individuals often are not provided
with genetic counseling or thorough informed consent.
• People may make important decisions about disease treatment or prevention based
on inaccurate, incomplete, or misunderstood information from their test results.
• There is currently little oversight or regulation of testing companies.
• Unproven or invalid tests can be misleading. There may not be enough scientific
evidence to link a particular genetic variation with a given disease or trait.
• Genetic privacy may be compromised if testing companies use your genetic

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 175

 information in an unauthorized way or if your data is stolen.
• The results of genetic testing may impact your ability to obtain life, disability, or long-
term care insurance.

Direct-to-consumer genetic testing provides only partial information about your health.
Other genetic and environmental factors, lifestyle choices, and family medical history
also affect the likelihood of developing many disorders. These factors would be
discussed during a consultation with a doctor or genetic counselor, but in many cases
they are not addressed when using at-home genetic tests.

Learn more about the pros and cons of direct-to-consumer genetic

testing:
National Human Genome Research Institute: Direct-to-Consumer Genetic Testing FAQ
(https://www.genome.gov/For-Health-Professionals/Provider-Genomics-Education-Reso
urces/Healthcare-Provider-Direct-to-Consumer-Genetic-Testing-FAQ)

Washington State Department of Health: Purchasing Genetic Testing- Buyers Beware! (

https://www.doh.wa.gov/YouandYourFamily/InfantsandChildren/HealthandSafety/Geneti
cServices/PurchasingGeneticTestingBuyersBeware)

GeneReviews: Resources for Genetics Professionals--Direct-to-Consumer Genetic

Testing (https://www.ncbi.nlm.nih.gov/books/NBK542335/#dtc_testing.Advantages)

Yale Medicine: Is an At-Home DNA Test an Ideal Gift, Really? (https://www.yalemedicin

e.org/stories/at-home-genetic-test-kit-holiday-gift/)

American College of Medical Genetics and Genomics (ACMG): Position statement on

direct-to-consumer genetic testing (https://www.acmg.net/docs/ACMG%20Revised%20
DTC%20Statement%20AOP%20Dec%202015.pdf)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 176

 8.5 How do I choose a direct-to-consumer genetic testing
company?
If you are interested in direct-to-consumer genetic testing, do some research into the
companies that offer these services. Questions that can help you assess the quality and
credibility of a testing company include:
• Does the company’s website appear professional? Do they have an app? Are both
secure? Does the company provide adequate information about the services it offers,
including sample reports, pricing, and methodology?
• Does the company have experienced genetics professionals, such as medical
geneticists and genetic counselors, on its staff? Does the company offer consultation
with a genetics professional if you have questions about your test results?
• Does the company explain which genetic variations it is testing for? Does it include
the scientific evidence linking those variations with a particular disease or trait? Are
the limitations of the test and the interpretation of results made clear?
• What kind of laboratory does the genetic testing, and is the laboratory inside or
outside the United States? Is the laboratory certified or accredited? For example,
does the laboratory meet U.S. federal regulatory standards called the Clinical
Laboratory Improvement Amendments (CLIA)? Is the test approved by the U.S.
Food and Drug Administration (FDA)?
• Does the company indicate how it will protect your privacy and keep your genetic
data safe? Does that information include both current privacy practices and what
may happen to your genetic data in the future?
• Does the company indicate who will have access to your data and how it may be
shared? Does it share or sell their customers’ genetic data for research or other
purposes? For some companies, much of their profit comes from selling large
amounts of participant data for research and drug development, not from selling
individual test kits.

Be sure to read and understand the “fine print” on the company’s website before
purchasing a direct-to-consumer genetic test. This detailed information, which is often
called the “terms of use” or “terms of service,” is a legally binding agreement between
you and the company providing the testing. It spells out what is included and excluded
in the service and details your rights and the company’s responsibilities. If you still have
questions, contact the company to get more information before you make a decision
about testing.

More information about factors to consider when choosing a direct-to-

consumer genetic testing company:
Harvard Law Bill of Health Blog: Considering Direct-to-Consumer Genetic Testing? Spit
with Caution. (https://blog.petrieflom.law.harvard.edu/2017/12/21/considering-direct-to-c
onsumer-genetic-testing-spit-with-caution/)

National Human Genome Research Institute: Regulation of Genetic Tests (https://www.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 177

genome.gov/about-genomics/policy-issues/Regulation-of-Genetic-Tests)

Personal Genetics Education Project: What is Consumer Genetics? (https://pged.org/dir

ect-to-consumer-genetic-testing/)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 178

 8.6 How is direct-to-consumer genetic testing done?
For most types of direct-to-consumer genetic testing, the process involves:

1. Purchasing a test
Test kits can be purchased online (and are shipped to your home) or at a store. The
price of some test kits includes the analysis and interpretation, while in other cases this
information is purchased separately.

2. Collecting the sample

Collection of the DNA sample usually involves spitting saliva into a tube or swabbing the
inside of your cheek and putting that swab into a tube. You then mail the sample as
directed by the company. In some cases, you will need to visit a health clinic to have
blood drawn.

3. Analyzing the sample

A laboratory will analyze the sample to look for particular genetic variations. The
variations included in the test depend on the purpose of the test.

4. Receiving results
In most cases, you will be able to access your results on a secure website or app. (You
will likely need to create an account on the testing company website to access results.)
Other test companies share results in the mail or over the phone. The results usually
include interpretation of what specific genetic variations may mean for your health or
ancestry. At some companies, you can request additional explanation from a genetic
counselor or other healthcare provider. This additional service may or may not involve
an extra cost. Some testing companies may update your results over time based on
new scientific information, such as a new genetic variant associated with a trait on their
test.

The test kit will include step-by-step instructions, so be sure you understand them
before you begin. If you have questions, contact the company before collecting your
sample.

Learn more about the direct-to-consumer genetic testing process:

National Society of Genetic Counselors: At-Home Genetic Testing (https://www.aboutge
neticcounselors.org/Reasons-to-See-a-Genetic-Counselor/At-Home-Genetic-Testing)

National Human Genome Research Institute: Direct-to-Consumer Genetic Testing FAQ

(https://www.genome.gov/For-Health-Professionals/Provider-Genomics-Education-Reso
urces/Healthcare-Provider-Direct-to-Consumer-Genetic-Testing-FAQ)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 179

 8.7 How much does direct-to-consumer genetic testing cost,
and is it covered by health insurance?
The price of direct-to-consumer genetic testing ranges from under a hundred dollars to
thousands dollars. The cost depends on how many genetic variations are analyzed (and
it will cost more if whole genome or whole exome sequencing is used), how extensive
the interpretation of results is, and whether other products, programs, or services are
included. Some companies charge separately for the sample collection kit and the
analysis, while others offer the sample collection and analysis as part of a package. In
some cases, consultation with a healthcare professional (such as a genetic counselor)
is included in the cost of testing; in others, it can be added for an additional fee. Before
you proceed with testing, make sure you know the total cost for all of the results,
support, and other services you expect to receive.

Direct-to-consumer genetic tests, even tests that provide information about health and
disease risk, are not covered by most health insurance plans. Because this testing is
done without a referral from a healthcare provider and is not considered “diagnostic”
(that is, it cannot be used to diagnose any disease or condition), health insurance
companies generally will not pay for it. However, the tests may be eligible for
reimbursement through flexible spending accounts (FSA) or health spending accounts
(HSA) if the testing included health information. If you decide to share your results with
your healthcare provider and he or she recommends additional testing or management,
that follow-up care may be covered by insurance.

Direct-to-consumer genetic tests that are unrelated (or indirectly related) to health, such
as ancestry testing and paternity testing, are typically not covered by FSAs, HSAs, or
health insurance plans.

Learn more about the costs of direct-to-consumer genetic testing:

MedlinePlus Genetics provides information about:
• What is the cost of genetic testing and how long does it take to get the results? (http
s://medlineplus.gov/genetics/understanding/testing/costresults/)
• Will health insurance cover the costs of genetic testing? (https://medlineplus.gov/ge
netics/understanding/testing/insurancecoverage/)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 180

 8.8 What do the results of direct-to-consumer genetic
testing mean?
Direct-to-consumer genetic testing can provide interesting information about your health,
traits, and ancestry. However, the results may not be clear-cut. Companies that
provide these tests often tell their customers that the results are for information,
education, and research purposes only—they are not meant to diagnose, prevent, or
treat any disease or health condition. It is useful to keep this distinction in mind when
interpreting your own test results.

Health and disease risk

The results of these genetic tests provide information about your chance of developing
certain diseases (such as celiac disease or Parkinson's disease) and the likelihood that
you have particular traits (such as dimples or lactose intolerance). These tests may also
provide information about how a person may respond to certain drugs
(pharmacogenomics). Test results are usually based on an analysis of one or more
genetic variations that are known or suspected to be associated with the disease or trait.
Direct-to-consumer genetic tests do not look at all genetic variants associated with
diseases or traits.

The results of tests to predict disease risk do not provide a “yes or no” answer about
whether a person will develop a given disease. Other factors, including genetic
variations that were not tested, environmental factors, and lifestyle choices (such as diet
and exercise) also contribute to disease risk in ways that may not be fully understood.
Therefore, a result showing an increased risk does not mean you will definitely develop
the disease, and a result showing a reduced risk does not mean you will never develop
the disease.

Ancestry or genealogy
The results of these tests give clues about major geographic areas that are your family’s
origins. These results are calculated on the basis of genetic variations that are more
common in people from certain areas of the world than in others.

Sometimes the results of ancestry testing are unexpected or inconsistent with what a
person understands about his or her family history. People who are closely related,
such as siblings, may receive slightly different information about their ancestry because
results are limited by the number and diversity of people who have submitted DNA
samples to a given direct-to-consumer genetic testing company. It is important to be
aware that receiving unexpected or ambiguous information about your background is a
potential risk with this type of testing.

Kinship
The results of these tests give information about individuals who are likely related to you.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 181

 (These individuals have also undergone testing, and the predictions are based on
similarities among DNA sequences.) These tests can uncover previously unknown
information about biological relationships among people (such as paternity). It is
important to be aware that receiving unexpected or ambiguous information about your
background or family is a potential risk with this type of testing.

Lifestyle
In most cases, direct-to-consumer lifestyle tests assess genetic variations related to
very specific traits, such as how your body converts the nutrients from food into energy
(metabolism), day/night (circadian) rhythm, or the senses of taste and smell. The
company may recommend specific diet or fitness programs, dietary supplements,
skincare products, or other products and services on the basis of your results. However,
in most cases the link between a given genetic variation and a complex trait like weight,
athletic performance, or sleep is indirect or unknown. Therefore, the results of these
tests can be challenging to interpret, and it can be difficult to predict whether a
recommended product or service will be helpful to you.

If you have questions about the meaning of your test results, professional support (such
as guidance from a genetic counselor) may be available from the company that
provided the test. You can also share questions about your results with your own
healthcare provider. Talk to your doctor before making any major changes in managing
your health, diet, or fitness after you receive results of a direct-to-consumer genetic test.

Read more about the issues raised by direct-to-consumer genetic test

results:
Kaiser Health News: My Grandmother Was Italian. Why Aren’t My Genes Italian? (https:
//khn.org/news/my-grandmother-was-italian-why-arent-my-genes-italian/)

PLOS DNA Science Blog: DNA Testing Kits as Holiday Gifts Can Bring Surprises (https:
//dnascience.plos.org/2017/12/14/dna-testing-kits-as-holiday-gifts-can-bring-surprises/)

British Journal of Sports Medicine (free full text from PubMed Central): Direct-to-
Consumer Genetic Testing for Predicting Sports Performance and Talent Identification:
Consensus Statement (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4680136/)

Stanford at the Tech: Going From DNA to Health Risk (https://genetics.thetech.org/ask-

a-geneticist/how-gwas-works)

Stanford at the Tech: Why Can’t a Genetic Test Predict Whether I Will Get Type 2
Diabetes? (https://genetics.thetech.org/ask-a-geneticist/genetic-tests-imprecise-comple
x-disease)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 182

 8.9 What can raw data from a direct-to-consumer genetic
test tell me?
In addition to providing various reports and analyses based on your genetics, some
direct-to-consumer genetic testing companies make your raw data available to
download. The raw data are your genotype—the particular A’s, C’s, T’s, and G’s of your
DNA—extracted from the sample you provided. These data are unique to you. Most
companies caution that the raw data are only for research or education and are not
suitable for medical purposes, such as diagnosing a disease.

It is challenging to interpret raw genotype data on your own. To help with this, several
online “third-party interpretation” services offer analysis and interpretation of the raw
data collected by another company. Third-party interpretation services can potentially
use your genetic data to provide you with more information about your disease risk,
traits, and ancestry. However, these services also have some risks and limitations:
• Relatively often, test results indicate an increased risk of disease when your risk is
not actually higher than that of the general population. These errors can cause
stress and anxiety.
• The results may include unexpected or upsetting information about your disease
risk or family relationships without any context or guidance.
• The raw data, once you download it and send it by e-mail or store it on your
computer, is no longer protected by the original service’s privacy measures.
• There is little regulation of third-party interpretation services.

As with any kind of genetic testing, it is important to assess the credibility of any
company you are considering and find out how it protects your privacy before submitting
your genetic information. Your healthcare provider can help you understand your results
and determine whether any follow-up testing would be useful.

Learn more about the interpretation of raw genetic data:

KQED/NPR: You Can Transform Your Genetic Ancestry Data Into Health Info, But Your
Results May Vary (https://www.kqed.org/science/18728/you-can-transform-your-genetic
-ancestry-data-into-health-info-but-your-results-may-vary)

Futurity: Home DNA Tests Put Gene Experts in an Awkward Spot (https://www.futurity.o
rg/home-dna-tests-1695142/)

Stanford at the Tech: Dangers of Converting Ancestry Data Into Health Data (https://gen
etics.thetech.org/ask-a-geneticist/dangers-converting-ancestry-data-health-data)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 183

 8.10 Can a direct-to-consumer genetic test tell me whether I
will develop cancer?
While a direct-to-consumer genetic test can estimate your risk, it cannot tell you for
certain whether you will or will not develop certain forms of cancer. Many other factors,
including sex, age, diet and exercise, ethnic background, a history of previous cancer,
hormonal and reproductive factors, and family history also contribute to a person’s
overall cancer risk.

The U.S. Food and Drug Administration (FDA) has allowed at least one direct-to-
consumer genetic testing company, 23andMe, to offer a test for cancer risk. The test
identifies specific genetic changes that are associated with particular cancers. For
example, it looks for three specific genetic variants (also known as mutations) in two
genes: BRCA1 and BRCA2. These variants are associated with an increased risk of
breast cancer, ovarian cancer, and potentially other forms of cancer in people of
Ashkenazi (eastern European) Jewish ancestry.

Researchers estimate that 5 to 10 percent of all cancers run in families. Some of these
cancers are associated with inherited mutations in particular genes, such as BRCA1 or
BRCA2. More than 1,000 variants in each of these genes have been associated with an
increased risk of cancer. However, the FDA-approved direct-to-consumer genetic test
analyzes only three of these genetic changes. The variants included in the test are
much more common in people of Ashkenazi Jewish background than in people of other
ethnicities, so if you are not of Ashkenazi Jewish heritage, the results may not be useful
to you.

The test offered by 23andMe also looks for two variants in the MUTYH gene. These
variants can cause a condition called MUTYH-associated polyposis (MAP; also known
as autosomal recessive familial adenomatous polyposis). MAP greatly increases a
person's risk of developing colorectal cancer, but it accounts for less than 1 percent of
colorectal cancer cases. The two variants included in the test are the most common
MAP-associated changes in people of European descent; however there are more than
100 variants in the MUTYH gene known to be associated with an increased risk of
developing cancer.

Because the variants included in these tests are uncommon, most people will have a
negative result. A negative result does not mean that you will never get cancer. Similarly,
a positive result (one that indicates a cancer-related genetic variation) does not mean
that you will definitely develop cancer.

Direct-to-consumer genetic testing for cancer risk can be stressful and anxiety-
producing. Health professional organizations and patient advocacy groups strongly
recommend that people considering genetic testing for cancer-associated gene variants,
including those included in direct-to-consumer genetic tests, talk with a genetic
counselor about the reasons they want to undergo testing and what the results could
mean for their health.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 184

Learn more about direct-to-consumer genetic testing for cancer risk:
U.S. Food and Drug Administration: FDA Authorizes, with Special Controls, Direct-to-
Consumer Test that Reports Three Mutations in the BRCA Breast Cancer Genes (https:
//www.fda.gov/news-events/press-announcements/fda-authorizes-special-controls-direc
t-consumer-test-reports-three-mutations-brca-breast-cancer)

American Cancer Society: What to Know Before Buying a Home DNA Test (https://www
.cancer.org/latest-news/what-to-know-before-buying-a-home-dna-test.html)

American Cancer Society: Should I Get Genetic Testing for Cancer Risk? (https://www.c
ancer.org/cancer/cancer-causes/genetics/should-i-get-genetic-testing-for-cancer-risk.ht
ml)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 185

 8.11 Can a direct-to-consumer genetic test tell me whether I
will develop Alzheimer's disease?
While a direct-to-consumer genetic test can estimate your risk, it cannot tell you for
certain whether you will or will not develop Alzheimer's disease. Variations in multiple
genes, together with lifestyle factors such as diet and exercise, all play a role in
determining a person’s risk.

The U.S. Food and Drug Administration (FDA) has allowed at least one direct-to-
consumer genetic testing company, 23andMe, to offer a test for Alzheimer's disease risk.
The test analyzes a gene called APOE. Certain variations in this gene are associated
with the likelihood of developing late-onset Alzheimer's disease (the most common form
of the condition, which begins after age 65). Specifically, the test allows you to find out
how many copies (zero, one, or two) you have of a version of the gene called the e4
allele. People who have zero copies of the e4 allele have the same risk of late-onset
Alzheimer's disease as the general population. The risk increases with the number of
copies of the e4 allele, so people with one copy have an increased chance of
developing the disease, and people with two copies have an even greater risk. However,
many people who have one or two copies of the e4 allele never develop Alzheimer's
disease, and many people with no copies of this allele ultimately get the disease.

Variations in the APOE gene are among many factors that influence a person’s overall
risk of developing Alzheimer's disease. Variations in many other genes, which are not
reported in the FDA-approved direct-to-consumer genetic test, also contribute to
disease risk. Additionally, there are risk factors for Alzheimer's disease that have yet to
be discovered. Therefore the APOE e4 allele represents only one piece of your overall
Alzheimer's disease risk.

Currently, there are no effective approaches for preventing Alzheimer's disease, and
while the disease can be treated, it has no cure. For these reasons, the National
Institute on Aging and patient advocacy groups strongly recommend that people
considering genetic testing for Alzheimer's disease, including direct-to-consumer
genetic testing, talk with a doctor or genetic counselor about the reasons they want to
undergo testing and how they would cope with the results.

Learn more about direct-to-consumer genetic testing for Alzheimer's

disease:
U.S. Food and Drug Administration: FDA Allows Marketing of First Direct-to-Consumer
Tests that Provide Genetic Risk Information for Certain Conditions (https://www.fda.gov/
news-events/press-announcements/fda-allows-marketing-first-direct-consumer-tests-pro
vide-genetic-risk-information-certain-conditions)

National Institute on Aging: Alzheimer’s Disease Genetics Fact Sheet (https://www.nia.n

ih.gov/health/alzheimers-disease-genetics-fact-sheet#testing)

Alzheimer’s Association: Genetic Testing (https://www.alz.org/media/Documents/alzhei

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 186

mers-dementia-genetic-testing-ts.pdf)

Alzheimer’s Society (UK): Genetics of Dementia: Genetic Testing (https://www.alzheime

rs.org.uk/about-dementia/risk-factors-and-prevention/types-genetic-testing)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 187

 8.12 What does it mean to have Neanderthal or Denisovan
DNA?
Several direct-to-consumer genetic testing companies report how much DNA a person
has inherited from prehistoric humans, such as Neanderthals and Denisovans. This
information is generally reported as a percentage that suggests how much DNA an
individual has inherited from these ancestors. The percentage of Neanderthal DNA in
modern humans is zero or close to zero in people from African populations, and is about
1 to 2 percent in people of European or Asian background. The percentage of
Denisovan DNA is highest in the Melanesian population (4 to 6 percent), lower in other
Southeast Asian and Pacific Islander populations, and very low or undetectable
elsewhere in the world.

Neanderthals were very early (archaic) humans who lived in Europe and Western Asia
from about 400,000 years ago until they became extinct about 40,000 years ago.
Denisovans are another population of early humans who lived in Asia and were distantly
related to Neanderthals. (Much less is known about the Denisovans because scientists
have uncovered fewer fossils of these ancient people.) The precise way that modern
humans, Neanderthals, and Denisovans are related is still under study. However,
research has shown that modern humans overlapped with Neanderthal and Denisovan
populations for a period, and that they had children together (interbred). As a result,
many people living today have a small amount of genetic material from these distant
ancestors.

Scientists have sequenced Neanderthal and Denisovan genomes from fossils

discovered in Europe and Asia. This genetic information is helping researchers learn
more about these early humans. Determining which areas of the genome are shared
with archaic humans, and which areas are different, will also help researchers find out
what differentiates modern humans from our closest extinct relatives.

In addition to the percentage of Neanderthal or Denisovan DNA, direct to-consumer

testing reports may include information about a few genetic variants inherited from
these ancestors that influence specific traits. Some studies have suggested that certain
genetic variations inherited from archaic humans may play roles in hair texture, height,
sensitivity of the sense of smell, immune responses, adaptations to high altitude, and
other characteristics in modern humans. These variations may also influence the risk of
developing certain diseases. However, other studies have not found the same
associations. The significance of Neanderthal or Denisovan genetic variants on disease
risk is still an area of active study, and most direct-to-consumer test results currently do
not include them.

While knowing how much DNA a person has in common with his or her Neanderthal or
Denisovan ancestors may be interesting, these data do not provide practical information
about a person’s current health or chances of developing particular diseases. Having
more or less DNA in common with archaic humans says nothing about how “evolved” a
person is, nor does it give any indication of strength or intelligence. For now, knowing
which specific genetic variants a person inherited from Neanderthal or Denisovan

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 188

ancestors provides only limited information about a few physical traits.

Scientific journal articles for further reading

Meyer M, Kircher M, Gansauge MT, Li H, Racimo F, Mallick S, Schraiber JG, Jay F,
Prüfer K, de Filippo C, Sudmant PH, Alkan C, Fu Q, Do R, Rohland N, Tandon A,
Siebauer M, Green RE, Bryc K, Briggs AW, Stenzel U, Dabney J, Shendure J, Kitzman
J, Hammer MF, Shunkov MV, Derevianko AP, Patterson N, Andrés AM, Eichler EE,
Slatkin M, Reich D, Kelso J, Pääbo S. A high-coverage genome sequence from an
archaic Denisovan individual. Science. 2012 Oct 12;338(6104):222-6. doi: 10.1126/
science.1224344. Epub 2012 Aug 30. PubMed: 22936568; Free full-text article from
PubMed Central: PMC3617501.

Pääbo S. The diverse origins of the human gene pool. Nat Rev Genet. 2015 Jun;16(6):
313-4. doi: 10.1038/nrg3954. PubMed: 25982166.

Sankararaman S, Mallick S, Dannemann M, Prüfer K, Kelso J, Pääbo S, Patterson N,

Reich D. The genomic landscape of Neanderthal ancestry in present-day humans.
Nature. 2014 Mar 20;507(7492):354-7. doi: 10.1038/nature12961. Epub 2014 Jan 29.
PubMed: 24476815. Free full-text article from PubMed Central: PMC4072735.

Skov L, Coll Macià M, Sveinbjörnsson G, Mafessoni F, Lucotte EA, Einarsdóttir MS,

Jonsson H, Halldorsson B, Gudbjartsson DF, Helgason A, Schierup MH, Stefansson K.
The nature of Neanderthal introgression revealed by 27,566 Icelandic genomes. Nature.
2020 Jun;582(7810):78-83. doi: 10.1038/s41586-020-2225-9. Epub 2020 Apr 22.
PubMed: 32494067.

Learn more about the genetics of Neanderthals and Denisovans:

The Smithsonian's Human Origins Program provides information about the genetics of
archaic humans and its relevance to modern humans:
• Homo neanderthalensis (https://humanorigins.si.edu/evidence/human-fossils/specie
s/homo-neanderthalensis)
• Ancient DNA and Neanderthals (https://humanorigins.si.edu/evidence/genetics/anci
ent-dna-and-neanderthals)

A news release about the complete sequencing of the Neanderthal genome (https://ww
w.genome.gov/27539119/2010-release-complete-neanderthal-genome-sequenced) is
available from the National Human Genome Research Institute.

The Max Planck Institute for Evolutionary Anthropology provides information and data
about the Denisovan genome (https://www.eva.mpg.de/genetics/genome-projects/denis
ova/index.html).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 189

 8.13 How do direct-to-consumer genetic testing companies
protect their customers’ privacy?
A person’s genetic data represent personal, private health information. If you are
considering direct-to-consumer genetic testing, it is important to know how the testing
company will protect your information. In particular, you should know how the company
will handle your sample (for example, saliva), how it plans to safeguard your data, and
whether and how your data will be used for secondary purposes (such as research or
advertising).

Most direct-to-consumer genetic testing companies provide detailed information on their

websites about their privacy and security practices. This information may be included in
a “privacy policy,” “privacy statement,” or “privacy center.” Be sure to read, understand,
and agree with this information before you start the testing process. If you have
questions, contact the company to get more information.

Questions that can help you assess a company’s privacy practices include:
• What does the company do with your sample once it has completed the analysis?
Will the sample be stored, shared, sold, or destroyed?
• Once you take the test, who owns your genetic data?
• How does the company safeguard your genetic data and other personal information
that you provide? Is it stored in a database that is protected from unauthorized
access? What happens if the database is hacked or otherwise compromised?
• Can you delete your results from the company’s database if you wish?
• Does the company use your information for internal research, advertising, or other
secondary purposes?
• Will the company share your genetic data or sell it to pharmaceutical or
biotechnology companies, academic institutions, or nonprofit organizations? If so,
will the shared data include other information that could identify you (such as your
name or date of birth)? For what purposes will your data be used? Will you be
informed when your data are shared or sold?
• If you do not want your genetic data shared, sold, or used for research, can you opt
out? What happens if you agree to share your information but want to opt out later?
• Will you be notified in the future if the company changes its privacy policies?
• What would happen to your sample and your genetic information if the company is
sold or goes out of business?

In some cases, even if a testing service promises not to share your genetic information
with others, they may be required by law to disclose the information to authorities in
response to a warrant, court order, or other legal requirement. Many companies now
provide explicit information about whether and how your genetic data may be accessed
by law enforcement officials. If you upload your data to public databases, such as those
administered by some third-party interpretation services, that information will be
available to law enforcement. Be sure to read and understand how your data may be

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 190

accessed by authorities before you submit your sample. Because everyone shares genetic
similarities with their relatives, it may have implications not only for your own privacy but
for that of people who are related to you.

Scientific journal articles for further reading

Berkman BE, Miller WK, Grady C. Is It Ethical to Use Genealogy Data to Solve Crimes?
Ann Intern Med. 2018 May 29. doi: 10.7326/M18-1348. [Epub ahead of print] PubMed:
29809242.

Ram N, Guerrini CJ, McGuire AL. Genealogy databases and the future of criminal
investigation. Science. 2018 Jun 8;360(6393):1078-1079. doi:10.1126/science.aau1083.
PubMed: 29880677.

Shen H, Ma J. Privacy Challenges of Genomic Big Data. Adv Exp Med Biol. 2017;1028:
139-148. doi: 10.1007/978-981-10-6041-0_8. Review. PubMed: 29058220.

Learn more about privacy issues related to direct-to-consumer

genetic testing:
Coalition for Genetic Data Protection: Privacy Best Practices for Consumer Genetic
Testing Services (https://fpf.org/wp-content/uploads/2018/07/Privacy-Best-Practices-for-
Consumer-Genetic-Testing-Services-FINAL.pdf)

Moffitt Cancer Center: Do DNA Test Kits Put Your Privacy on the Line? (https://moffitt.or
g/endeavor/archive/do-dna-test-kits-put-your-privacy-on-the-line/)

Harvard Law Bill of Health Blog: Transparency and Direct-to-Consumer Genetic Testing
Companies (https://blog.petrieflom.law.harvard.edu/2016/11/22/transparency-and-direct
-to-consumer-genetic-testing-companies/)

The Hastings Center: Addressing Questions About DTC Genetic Tests and Privacy (http
s://www.thehastingscenter.org/addressing-questions-dtc-genetic-tests-privacy/)

Proceedings of the National Academy of Sciences: Study uncovers new privacy worries
for direct-to-consumer DNA testing (https://www.pnas.org/post/journal-club/study-uncov
ers-new-privacy-worries-for-direct-to-consumer-dna-testing)

Personal Genetics Education Project: Genetics, Law Enforcement, and Crime (https://p
ged.org/genetics-and-crime/)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 191

 8.14 Can the results of direct-to-consumer genetic testing
affect my ability to get insurance?
Passed in 2008, a federal law called the Genetic Information Nondiscrimination Act
(GINA) made it illegal for health insurance providers in the United States to use genetic
information in decisions about a person's health insurance eligibility or coverage. This
means that health insurance companies cannot use the results of a direct-to-consumer
genetic test (or any other genetic test) to deny coverage or require you to pay higher
premiums. However, GINA does not apply when an employer has fewer than 15
employees.

GINA does not apply to other forms of insurance, such as disability insurance, long-term
care insurance, or life insurance. However, some states have laws that cover these
forms of insurance. Unless prohibited by state laws, companies that offer these policies
have the right to request medical information, including the results of any genetic testing,
when making decisions about coverage and rates. Some of these companies request
information about genetic testing as part of their application process, but others do not.
It is unclear whether genetic information, including the results of direct-to-consumer
genetic testing, will become a standard part of the risk assessment that insurance
companies undertake when making coverage decisions.

You should weigh the possible benefits and risks of direct-to-consumer genetic testing,
including potential impacts on insurance eligibility and coverage, before you start the
testing process.

Learn more about the implications of direct-to-consumer genetic

testing in insurance coverage:
National Human Genome Research Institute: Genetic Discrimination (https://www.geno
me.gov/about-genomics/policy-issues/Genetic-Discrimination)

Genome Statute and Legislation Database (https://www.genome.gov/about-genomics/p

olicy-issues/Genome-Statute-Legislation-Database)

Genetic Alliance: Genetic Discrimination (http://www.geneticalliance.org/advocacy/polic

yissues/geneticdiscrimination)

Wharton Public Policy Podcast: Why Genetic Testing Is a ‘Perfect Storm’ for Insurers (ht
tps://knowledge.wharton.upenn.edu/article/why-genetic-testing-is-a-perfect-storm-for-ins
urers/)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 192

 8.15 Where can I read more about the diseases and traits
covered in my direct-to-consumer genetic testing report?
Learn more from MedlinePlus Genetics about some of the health conditions and traits
that may be included in your report. Each plain-language summary provides information
about the condition’s major features, frequency, causes, and inheritance. You will also
find links to other reputable sources of online health information.

Health conditions
BRCA1- or BRCA2-related breast cancer and ovarian cancer

Familial adenomatous polyposis, including MUTYH-associated polyposis

Age-related macular degeneration

Alpha-1 antitrypsin deficiency

Celiac disease

Familial hypercholesterolemia

Glucose-6-phosphate dehydrogenase deficiency, also called G6PD deficiency

Hereditary hemochromatosis

Transthyretin amyloidosis

Hereditary thrombophilia: prothrombin thrombophilia and factor V Leiden thrombophilia

Alzheimer's disease

Parkinson's disease

Wellness
Lactose intolerance

Traits
Cheek dimples

Eye color

Hair texture

Hair color (light or dark hair)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 193

Carrier status
Autosomal recessive spastic ataxia of Charlevoix-Saguenay, also called ARSACS

Andermann syndrome, also called agenesis of the corpus callosum with peripheral
neuropathy

Polycystic kidney disease

Beta thalassemia

Bloom syndrome

Canavan disease

PMM2-congenital disorder of glycosylation, also called PMM2-CDG

Cystic fibrosis

D-bifunctional protein deficiency

Dihydrolipoamide dehydrogenase deficiency

Familial dysautonomia

Congenital hyperinsulinism, also called familial hyperinsulinism

Familial Mediterranean fever

Fanconi anemia

GRACILE syndrome

Gaucher disease

Glycogen storage disease type I

Hereditary fructose intolerance

Junctional epidermolysis bullosa

Leigh syndrome

Limb-girdle muscular dystrophy

Medium-chain acyl-CoA dehydrogenase deficiency, also called MCAD deficiency

Maple syrup urine disease

Mucolipidosis type IV

CLN5 disease, also called neuronal ceroid lipofuscinosis (CLN5-related)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 194

CLN1 disease, also called neuronal ceroid lipofuscinosis (PPT1-related)

Niemann-Pick disease

Nijmegen breakage syndrome

Nonsyndromic hearing loss

Pendred syndrome

Phenylketonuria

Primary hyperoxaluria

Pyruvate kinase deficiency

Rhizomelic chondrodysplasia punctata

Sialic acid storage disease, including Salla disease

Sickle cell disease, also called sickle cell anemia

Sjögren-Larsson syndrome

Tay-Sachs disease

Tyrosinemia

Usher syndrome

Zellweger spectrum disorder, also called Zellweger syndrome spectrum

Pharmacogenetics
CYP2C19 drug metabolism

For more help understanding your test results:

MedlinePlus Genetics provides information about:
• How can I find a genetics professional in my area? (https://medlineplus.gov/genetic
s/understanding/consult/findingprofessional/)
• What happens during a genetic consultation? (https://medlineplus.gov/genetics/und
erstanding/consult/expectations/)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 195

 9
Gene Therapy and Other Medical Advances
9.1 What is gene therapy?
Gene therapy is a medical approach that treats or prevents disease by correcting the
underlying genetic problem. Gene therapy techniques allow doctors to treat a disorder
by altering a person’s genetic makeup instead of using drugs or surgery.

The earliest method of gene therapy, often called gene transfer or gene addition, was
developed to:
• Introduce a new gene into cells to help fight a disease.
• Introduce a non-faulty copy of a gene to stand in for the altered copy causing
disease.

Later studies led to advances in gene therapy techniques. A newer technique, called
genome editing (an example of which is CRISPR-Cas9), uses a different approach to
correct genetic differences. Instead of introducing new genetic material into cells,
genome editing introduces molecular tools to change the existing DNA in the cell.
Genome editing is being studied to:
• Fix a genetic alteration underlying a disorder, so the gene can function properly.
• Turn on a gene to help fight a disease.
• Turn off a gene that is functioning improperly.
• Remove a piece of DNA that is impairing gene function and causing disease.

Gene therapies are being used to treat a small number of diseases, including an eye
disorder called Leber congenital amaurosis and a muscle disorder called spinal
muscular atrophy. Many more gene therapies are undergoing research to make sure
that they will be safe and effective. Genome editing is a promising technique also under
study that doctors hope to use soon to treat disorders in people.

For general information about gene therapy:

MedlinePlus offers a list of links to information about genes and gene therapy (https://m
edlineplus.gov/genesandgenetherapy.html).

The Genetic Science Learning Center at the University of Utah provides an interactive
introduction to gene therapy (https://learn.genetics.utah.edu/content/genetherapy/) and
a discussion of several diseases for which gene therapy has been successful (https://le
arn.genetics.utah.edu/content/genetherapy/success/).

The Centre for Genetics Education provides an introduction to gene therapy and other
therapeutics (https://www.genetics.edu.au/SitePages/Gene-therapy-advanced-therapeu
tics.aspx), including a discussion of ethical and safety considerations.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 196

The National Heart, Lung, and Blood Institute describes the approaches to gene therapy
and how they work (https://www.nhlbi.nih.gov/health-topics/genetic-therapies).

Your Genome from the Wellcome Genome Campus provides an introduction to gene
therapy and describes several techniques (https://www.yourgenome.org/facts/what-is-g
ene-therapy).

KidsHealth from Nemours offers a fact sheet called Gene Therapy and Children (https://
kidshealth.org/en/parents/gene-therapy.html).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 197

 9.2 How does gene therapy work?
Gene therapy works by altering the genetic code to recover the functions of critical
proteins. Proteins are the workhorses of the cell and the structural basis of the body’s
tissues. The instructions for making proteins are carried in a person’s genetic code, and
variants (or mutations) in this code can impact the production or function of proteins that
may be critical to how the body works. Fixing or compensating for disease-causing
genetic changes may recover the role of these important proteins and allow the body to
function as expected.

Gene therapy can compensate for genetic alterations in a couple different ways.
• Gene transfer therapy introduces new genetic material into cells. If an altered gene
causes a necessary protein to be faulty or missing, gene transfer therapy can
introduce a normal copy of the gene to recover the function of the protein.
Alternatively, the therapy can introduce a different gene that provides instructions for
a protein that helps the cell function normally, despite the genetic alteration.
• Genome editing is a newer technique that may potentially be used for gene therapy.
Instead of adding new genetic material, genome editing introduces gene-editing
tools that can change the existing DNA in the cell. Genome editing technologies
allow genetic material to be added, removed, or altered at precise locations in the
genome. CRISPR-Cas9 is a well-known type of genome editing.

Genetic material or gene-editing tools that are inserted directly into a cell usually do not
function. Instead, a carrier called a vector is genetically engineered to carry and deliver
the material. Certain viruses are used as vectors because they can deliver the material
by infecting the cell. The viruses are modified so they can't cause disease when used in
people. Some types of virus, such as retroviruses, integrate their genetic material
(including the new gene) into a chromosome in the human cell. Other viruses, such as
adenoviruses, introduce their DNA into the nucleus of the cell, but the DNA is not
integrated into a chromosome. Viruses can also deliver the gene-editing tools to the
nucleus of the cell.

The vector can be injected or given intravenously (by IV) directly into a specific tissue in
the body, where it is taken up by individual cells. Alternately, a sample of the patient's
cells can be removed and exposed to the vector in a laboratory setting. The cells
containing the vector are then returned to the patient. If the treatment is successful, the
new gene delivered by the vector will make a functioning protein or the editing
molecules will correct a DNA error and restore protein function.

Gene therapy with viral vectors has been successful, but it does carry some risk.
Sometimes the virus triggers a dangerous immune response. In addition, vectors that
integrate the genetic material into a chromosome can cause errors that lead to cancer.
Researchers are developing newer technologies that can deliver genetic material or
gene-editing tools without using viruses. One such technique uses special structures
called nanoparticles as vectors to deliver the genetic material or gene-editing
components into cells. Nanoparticles are incredibly small structures that have been
developed for many uses. For gene therapy, these tiny particles are designed with

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 198

specific characteristics to target them to particular cell types. Nanoparticles are less likely to
cause immune reactions than viral vectors, and they are easier to design and modify for
specific purposes.

Researchers continue to work to overcome the many technical challenges of gene

therapy. For example, scientists are finding better ways to deliver genes or gene-editing
tools and target them to particular cells. They are also working to more precisely control
when the treatment is functional in the body.

Scientific journal articles for further reading

Bulcha JT, Wang Y, Ma H, Tai PWL, Gao G. Viral vector platforms within the gene
therapy landscape. Signal Transduct Target Ther. 2021 Feb 8;6(1):53. doi: 10.1038/
s41392-021-00487-6. PMID: 33558455. Free full-text article from PubMed Central:
PMC7868676.

Duan L, Ouyang K, Xu X, Xu L, Wen C, Zhou X, Qin Z, Xu Z, Sun W, Liang Y.

Nanoparticle Delivery of CRISPR/Cas9 for Genome Editing. Front Genet. 2021 May 12;
12:673286. doi: 10.3389/fgene.2021.673286. PubMed: 34054927. Free full-text article
from PubMed Central: PMC8149999.

A new gene is inserted directly into a cell. A carrier called a vector is genetically
engineered to deliver the gene. An adenovirus introduces the DNA into the nucleus of
the cell, but the DNA is not integrated into a chromosome. (Figure 9.1)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 199

 FIGURE 9.1: A new gene is inserted directly into a cell. A carrier
called a vector is genetically engineered to deliver the gene. An
adenovirus introduces the DNA into the nucleus of the cell, but the
DNA is not integrated into a chromosome.

For more information about how gene therapy works:

Boston Children’s Hospital summarizes the evolution of gene therapy techniques (https:
//answers.childrenshospital.org/gene-therapy-history/).

The Genetic Science Learning Center at the University of Utah provides information
about various technical aspects of gene therapy in Gene Delivery: Tools of the Trade (ht
tps://learn.genetics.utah.edu/content/genetherapy/tools/). They also discuss other
approaches to gene therapy (https://learn.genetics.utah.edu/content/genetherapy/appro
aches/) and offer a related learning activity called Space Doctor (https://learn.genetics.u
tah.edu/content/genetherapy/doctor/).

The American Society of Gene and Cell Therapy offers an in-depth description of the
different types of viral vectors used in gene therapy (https://patienteducation.asgct.org/g
ene-therapy-101/vectors-101).

Penn Medicine's OncoLink describes how gene therapy works and how it is
administered to patients (https://www.oncolink.org/cancer-treatment/immunotherapy/wh
at-is-gene-therapy).

The basics of nanoparticles and their use in medicine (https://askabiologist.asu.edu/tiny-

medicine) are explained in the Ask a Biologist feature from Arizona State University.

Your Genome from the Wellcome Genome campus explains the first gene therapy trial
to treat a condition called severe combined immunodeficiency (SCID) (https://www.your
genome.org/stories/treating-the-bubble-babies-gene-therapy-in-use). It also describes
other applications for gene therapy.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 200

 9.3 Is gene therapy safe?
The first gene therapy trial was run more than thirty years ago. The earliest studies
showed that gene therapy could have very serious health risks, such as toxicity,
inflammation, and cancer. Since then, researchers have studied the mechanisms and
developed improved techniques that are less likely to cause dangerous immune
reactions or cancer. Because gene therapy techniques are relatively new, some risks
may be unpredictable; however, medical researchers, institutions, and regulatory
agencies are working to ensure that gene therapy research, clinical trials, and approved
treatments are as safe as possible.

Comprehensive federal laws, regulations, and guidelines help protect people who
participate in research studies (called clinical trials). The U.S. Food and Drug
Administration (FDA) regulates all gene therapy products in the United States and
oversees research in this area. Researchers who wish to test an approach in a clinical
trial must first obtain permission from the FDA. The FDA has the authority to reject or
suspend clinical trials that are suspected of being unsafe for participants.

The National Institutes of Health (NIH) also plays an important role in ensuring the
safety of gene therapy research. NIH provides guidelines for investigators and
institutions (such as universities and hospitals) to follow when conducting clinical trials
with gene therapy. These guidelines state that clinical trials at institutions receiving NIH
funding for this type of research must be registered with the NIH Office of Biotechnology
Activities. The protocol, or plan, for each clinical trial is then reviewed by the NIH
Recombinant DNA Advisory Committee (RAC) to determine whether it raises medical,
ethical, or safety issues that warrant further discussion at a RAC public meeting.

An Institutional Review Board (IRB) and an Institutional Biosafety Committee (IBC) must
approve each gene therapy clinical trial before it can be carried out. An IRB is a
committee of scientific and medical advisors and consumers that reviews all research
within an institution. An IBC is a group that reviews and approves an institution's
potentially hazardous research studies. Multiple levels of evaluation and oversight
ensure that safety concerns are a top priority in the planning and carrying out of gene
therapy research.

The clinical trial process occurs in three phases. Phase I studies determine if a
treatment is safe for people and identify its side effects. Phase II studies determine if the
treatment is effective, meaning whether it works. Phase III studies compare the new
treatment to the current treatments available. Doctors want to know whether the new
treatment works better or has fewer side effects than the standard treatment. The FDA
reviews the results of the clinical trial. If it determines that the benefits of the new
treatment outweigh the side effects, it approves the therapy, and doctors can use it to
treat a disorder.

Successful clinical trials have led to the approval of a small number of gene therapies,
including therapies to treat inherited disorders like spinal muscular atrophy and Leber
congenital amaurosis.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 201

For more information about the safety and oversight of gene therapy:
The Genetic Science Learning Center at the University of Utah explains challenges
related to gene therapy (https://learn.genetics.utah.edu/content/genetherapy/challenges
/).

The NIH's Office of Biotechnology Activities provides NIH guidelines for biosafety (https:
//osp.od.nih.gov/biotechnology/nih-guidelines/).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 202

 9.4 What are the ethical issues surrounding gene therapy?
Because gene therapy involves making changes to the body’s basic building blocks
(DNA), it raises many unique ethical concerns. The ethical questions surrounding gene
therapy and genome editing include:
• How can “good” and “bad” uses of these technologies be distinguished?
• Who decides which traits are normal and which constitute a disability or disorder?
• Will the high costs of gene therapy make it available only to the wealthy?
• Could the widespread use of gene therapy make society less accepting of people
who are different?
• Should people be allowed to use gene therapy to enhance basic human traits such
as height, intelligence, or athletic ability?

Current research on gene therapy treatment has focused on targeting body (somatic)
cells such as bone marrow or blood cells. This type of genetic alteration cannot be
passed to a person’s children. Gene therapy could be targeted to egg and sperm cells
(germ cells), however, which would allow the genetic changes to be passed to future
generations. This approach is known as germline gene therapy.

The idea of these germline alterations is controversial. While it could spare future
generations in a family from having a particular genetic disorder, it might affect the
development of a fetus in unexpected ways or have long-term side effects that are not
yet known. Because people who would be affected by germline gene therapy are not
yet born, they can’t choose whether to have the treatment. Because of these ethical
concerns, the U.S. Government does not allow federal funds to be used for research on
germline gene therapy in people.

For more information about the ethical issues raised by gene therapy:
The National Human Genome Research Institute discusses the ethical concerns of
genome editing (https://www.genome.gov/about-genomics/policy-issues/Genome-Editin
g/ethical-concerns).

A debate of the ethics of germline gene therapy (https://www.yourgenome.org/debates/i

s-germline-gene-therapy-ethical) is presented by yourgenome.org from the Wellcome
Genome Campus.

A discussion of the ethics of gene therapy and genetic engineering (https://medicine.mis

souri.edu/centers-institutes-labs/health-ethics/faq/gene-therapy) is available from the
University of Missouri Center for Health Ethics.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 203

 9.5 Is gene therapy available to treat my disorder?
Gene therapy is currently available primarily in a research setting. The U.S. Food and
Drug Administration (FDA) has approved only a small number of gene therapy products
for sale in the United States. For example, FDA-approved gene therapies are available
for conditions that include a rare eye disorder called Leber congenital amaurosis, a form
of skin cancer known as melanoma, and a genetic muscle condition called spinal
muscular atrophy. Other genetic therapies have been approved for blood cell cancers
such as lymphoma and multiple myeloma. Gene therapies to treat additional conditions
have been approved in other countries.

Hundreds of research studies (clinical trials) are under way to test gene therapy as a
treatment for genetic conditions, cancer, and HIV/AIDS. If you are interested in
participating in a clinical trial, talk with your doctor or a genetics professional about how
to participate.

For information about gene therapy clinical trials:

You can also search for clinical trials online. ClinicalTrials.gov (https://clinicaltrials.gov/),
a service of the National Institutes of Health, provides easy access to information about
clinical trials. You can search for a specific clinical trial or browse by health condition or
sponsor. You may wish to refer to a list of gene therapy clinical trials (https://clinicaltrials
.gov/search?term=%22gene+therapy%22) or gene or genome editing clinical trials (http
s://clinicaltrials.gov/ct2/results?cond=&term=%22gene+editing%22+OR+%22geno
me+editing%22) that are accepting (or will accept) participants.

An explanation of the clinical trial process and how to find a clinical trial is presented by
the American Society of Gene and Cell Therapy (https://patienteducation.asgct.org/gen
e-therapy-101/clinical-trials-process).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 204

 9.6 What are CAR T cell therapy, RNA therapy, and other
genetic therapies?
Several treatments have been developed that involve genetic material but are typically
not considered gene therapy. Some of these methods alter DNA for a slightly different
use than gene therapy. Others do not alter genes themselves, but they change whether
or how a gene’s instructions are carried out to make proteins.

Cell-based gene therapy

CAR T cell therapy (or chimeric antigen receptor T cell therapy) is an example of cell-
based gene therapy. This type of treatment combines the technologies of gene therapy
and cell therapy. Cell therapy introduces cells to the body that have a particular function
to help treat a disease. In cell-based gene therapy, the cells have been genetically
altered to give them the special function. CAR T cell therapy introduces a gene to a
person’s T cells, which are a type of immune cell. This gene provides instructions for
making a protein, called the chimeric antigen receptor (CAR), that attaches to cancer
cells. The modified immune cells can specifically attack cancer cells.

RNA therapy

Several techniques, called RNA therapies, use pieces of RNA, which is a type of
genetic material similar to DNA, to help treat a disorder. In many of these techniques,
the pieces of RNA interact with a molecule called messenger RNA (or mRNA for short).
In cells, mRNA uses the information in genes to create a blueprint for making proteins.
By interacting with mRNA, these therapies influence how much protein is produced from
a gene, which can compensate for the effects of a genetic alteration. Examples of these
RNA therapies include antisense oligonucleotide (ASO), small interfering RNA (siRNA),
and microRNA (miRNA) therapies. An RNA therapy called RNA aptamer therapy
introduces small pieces of RNA that attach directly to proteins to alter their function.

Epigenetic therapy

Another gene-related therapy, called epigenetic therapy, affects epigenetic changes in

cells. Epigenetic changes are specific modifications (often called “tags”) attached to
DNA that control whether genes are turned on or off. Abnormal patterns of epigenetic
modifications alter gene activity and, subsequently, protein production. Epigenetic
therapies are used to correct epigenetic errors that underlie genetic disorders.

Scientific journal articles for further reading

Kim YK. RNA Therapy: Current Status and Future Potential. Chonnam Med J. 2020
May;56(2):87-93. doi: 10.4068/cmj.2020.56.2.87. Epub 2020 May 25. PubMed:
32509554. Free full-text article from PubMed Central: PMC7250668.

Lu Y, Chan YT, Tan HY, Li S, Wang N, Feng Y. Epigenetic regulation in human cancer:
the potential role of epi-drug in cancer therapy. Mol Cancer. 2020 Apr 27;19(1):79. doi:
10.1186/s12943-020-01197-3. 32340605. Free full-text article from PubMed Central:

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 205

PMC7184703.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 206

 9.7 What are mRNA vaccines and how do they work?
Vaccines help prevent infection by preparing the body to fight foreign invaders (such as
bacteria, viruses, or other pathogens). All vaccines introduce into the body a harmless
piece of a particular bacteria or virus, triggering an immune response. Most vaccines
contain a weakened or dead bacteria or virus. However, scientists have developed a
new type of vaccine that uses a molecule called messenger RNA (mRNA) rather than
part of an actual bacteria or virus. Messenger RNA is a type of RNA that is necessary
for protein production. Once cells finish making a protein, they quickly break down the
mRNA. mRNA from vaccines does not enter the nucleus and does not alter DNA.

mRNA vaccines work by introducing a piece of mRNA that corresponds to a viral protein,
usually a small piece of a protein found on the virus’s outer membrane. (Individuals
who get an mRNA vaccine are not exposed to the virus, nor can they become infected
with the virus by the vaccine.) By using this mRNA, cells can produce the viral protein.
As part of a normal immune response, the immune system recognizes that the protein is
foreign and produces specialized proteins called antibodies. Antibodies help protect the
body against infection by recognizing individual viruses or other pathogens, attaching to
them, and marking the pathogens for destruction. Once produced, antibodies remain in
the body, even after the body has rid itself of the pathogen, so that the immune system
can quickly respond if exposed again. If a person is exposed to a virus after receiving
mRNA vaccination for it, antibodies can quickly recognize it, attach to it, and mark it for
destruction before it can cause serious illness.

Like all vaccines in the United States, mRNA vaccines require authorization or approval
from the Food and Drug Administration (FDA) before they can be used. Currently
vaccines for COVID-19, the disease caused by the SARS-CoV-2 coronavirus, are the
only authorized or approved mRNA vaccines. These vaccines use mRNA that directs
cells to produce copies of a protein on the outside of the coronavirus known as the “
spike protein”. Researchers are studying how mRNA might be used to develop vaccines
for additional diseases.

Scientific journal articles for further reading

Jain S, Venkataraman A, Wechsler ME, Peppas NA. Messenger RNA-based vaccines:
Past, present, and future directions in the context of the COVID-19 pandemic. Adv Drug
Deliv Rev. 2021 Oct 9;179:114000. doi: 10.1016/j.addr.2021.114000. Epub ahead of
print. PMID: 34637846; PMCID: PMC8502079.

Verbeke R, Lentacker I, De Smedt SC, Dewitte H. The dawn of mRNA vaccines: The
COVID-19 case. J Control Release. 2021 May 10;333:511-520. doi: 10.1016/j.jconrel.
2021.03.043. Epub 2021 Mar 30. PMID: 33798667; PMCID: PMC8008785.

Microscopic image of SARS-CoV-2, the virus that causes COVID-19. Spike proteins are
seen surrounding the outer membrane of each virus particle. (Figure 9.2)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 207

 FIGURE 9.2: Microscopic image of four SARS-CoV-2 virus particles, the
virus that causes COVID-19. Spike proteins are seen surrounding the outer
membrane of each virus particle.

For more information about mRNA vaccines:

MedlinePlus offers many additional resources with information about mRNA vaccines,
specifically relating to their use in COVID-19
• MedlinePlus: Health Topic: COVID-19 Vaccines (https://medlineplus.gov/covid19va
ccines.html)
• MedlinePlus: Encyclopedia: COVID-19 vaccines (https://medlineplus.gov/ency/articl
e/007775.htm)
• MedlinePlus: Drugs and Supplements: COVID-19 Vaccine, mRNA (Pfizer-BioNTech)
(https://medlineplus.gov/druginfo/meds/a621003.html)
• MedlinePlus: Drugs and Supplements: COVID-19 Vaccine, mRNA (Moderna) (https
://medlineplus.gov/druginfo/meds/a621002.html)

The National Institute of Allergy and Infectious Diseases provides in-depth information (
https://www.niaid.nih.gov/diseases-conditions/coronavirus-vaccines-prevention) about
the COVID-19 vaccines.

The Centers for Disease Control and Prevention has a fact sheet (https://www.cdc.gov/c
oronavirus/2019-ncov/vaccines/different-vaccines/mRNA.html) on mRNA vaccines.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 208

 10
Genomic Research
10.1 What are single nucleotide polymorphisms (SNPs)?
Single nucleotide polymorphisms, frequently called SNPs (pronounced “snips”), are the
most common type of genetic variation among people. Each SNP represents a
difference in a single DNA building block, called a nucleotide. For example, a SNP may
replace the nucleotide cytosine (C) with the nucleotide thymine (T) in a certain stretch of
DNA.

SNPs occur normally throughout a person’s DNA. They occur almost once in every 1,
000 nucleotides on average, which means there are roughly 4 to 5 million SNPs in a
person's genome. These variations occur in many individuals; to be classified as a SNP,
a variant is found in at least 1 percent of the population. Scientists have found more
than 600 million SNPs in populations around the world.

Most commonly, SNPs are found in the DNA between genes. They can act as biological
markers, helping scientists locate genes that are associated with disease. When SNPs
occur within a gene or in a regulatory region near a gene, they may play a more direct
role in disease by affecting the gene’s function.

Most SNPs have no effect on health or development. Some of these genetic differences,
however, have proven to be very important in the study of human health. SNPs help
predict an individual’s response to certain drugs, susceptibility to environmental factors
such as toxins, and risk of developing diseases. SNPs can also be used to track the
inheritance of disease-associated genetic variants within families. Research is ongoing
to identify SNPs associated with complex diseases such as heart disease, diabetes,
and cancer.

For more information about SNPs:

An audio definition of SNPs (https://www.genome.gov/genetics-glossary/Single-Nucleoti
de-Polymorphisms) is available from the National Human Genome Research Institute’s
Talking Glossary of Genetic Terms.

How scientists locate SNPs in the genome (https://learn.genetics.utah.edu/content/preci

sion/snips/) is explained by the University of Utah Genetic Science Learning Center.

For people interested in more technical data, the National Library of Medicine maintains
a frequently updated resource at NCBI of a database of single nucleotide
polymorphisms (dbSNP) (https://www.ncbi.nlm.nih.gov/SNP/)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 209

 10.2 What are genome-wide association studies?
Genome-wide association studies (GWAS) help scientists identify genes associated
with a particular disease (or another trait). This method studies the entire set of DNA
(the genome) of a large group of people, searching for small variations, called single
nucleotide polymorphisms or SNPs (pronounced “snips”). Each study can look at
hundreds or thousands of SNPs at the same time. Scientists can then identify SNPs
that occur more frequently in people with a certain disease than in people without it.
These SNPs are said to be associated with the disease, and they can help researchers
pinpoint genes that are likely involved in disease development. Because genome-wide
association studies examine SNPs across the genome, they represent a promising way
to study complex, common diseases in which many genetic variations contribute to a
person’s risk. This approach has identified SNPs associated with several complex
conditions including diabetes, heart disease, Parkinson's disease, and Crohn's disease.
SNPs have also been associated with a person’s response to certain drugs and
susceptibility to certain environmental factors such as toxins. Researchers hope that
future genome-wide association studies will identify additional SNPs associated with
chronic diseases and drug effects.

Through genome-wide association studies, individual SNPs are identified that account
for only a small percentage of disease risk. Together, large numbers of SNPs across
the genome can help determine the overall risk of developing a disease or responding
to particular drugs. Researchers can use information learned from genome-wide
association studies to predict more accurately which prevention and treatment
strategies will work in which groups of people, an important step in precision medicine.

For more information about genome-wide association studies:

The National Human Genome Research Institute provides a detailed explanation of
genome-wide association studies (https://www.genome.gov/about-genomics/fact-sheets
/Genome-Wide-Association-Studies-Fact-Sheet). In addition, the National Human
Genome Research Institute and the European Bioinformatics Institute jointly provide a
Catalog of Published Genome-Wide Association Studies (https://www.ebi.ac.uk/gwas/).

ClinicalTrials.gov (https://clinicaltrials.gov/), a service of the National Institutes of Health,

provides easy access to information about clinical trials. This site offers the option to
search for a specific clinical trial or browse by health condition or sponsor. They also
provide a list of genome-wide association studies (https://clinicaltrials.gov/search?term=
GWAS+OR+%22Genome+Wide+Association%22) that are accepting (or will accept)
participants.

For more technical information, the NCBI’s Database of Genotypes and Phenotypes
(dbGaP) (https://www.ncbi.nlm.nih.gov/gap/) contains data from genome-wide
association studies.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 210

 10.3 What is pharmacogenomics?
Pharmacogenomics is the study of how genes affect a person’s response to drugs. This
field combines pharmacology (the science of drugs) and genomics (the study of genes
and their functions) to develop effective, safe medications that can be prescribed based
on a person’s genetic makeup.

Many drugs that are currently available are “one size fits all,” but they don't work the
same way for everyone. It can be difficult to predict who will benefit from a medication,
who will not respond at all, and who will experience negative side effects (called
adverse drug reactions). Adverse drug reactions are a significant cause of
hospitalizations and deaths in the United States.

Researchers are learning how variants in genes affect the body’s response to
medications. These genetic differences will be used to predict whether a medication will
be effective for a particular person and which dose will help prevent adverse drug
reactions. Conditions that affect a person’s response to certain drugs include
clopidogrel resistance, warfarin sensitivity, warfarin resistance, malignant hyperthermia,
Stevens-Johnson syndrome/toxic epidermal necrolysis, and thiopurine S-
methyltransferase deficiency.

The field of pharmacogenomics is growing, and new approaches are under study in
clinical trials. In the future, pharmacogenomics will be used to develop tailored drugs to
treat a wide range of health problems, including cardiovascular disease, Alzheimer's
disease, cancer, and asthma.

For more information about pharmacogenomics:

MedlinePlus provides additional details about pharmacogenetic tests (https://medlineplu
s.gov/lab-tests/pharmacogenetic-tests/).

The National Institute of General Medical Sciences offers a list of Frequently Asked
Questions about Pharmacogenomics (https://www.nigms.nih.gov/education/fact-sheets/
Pages/pharmacogenomics.aspx).

A pharmacogenomics fact sheet (https://www.genome.gov/dna-day/15-ways/pharmaco

genomics) and a list of Frequently Asked Questions about Pharmacogenomics (https://
www.genome.gov/FAQ/Pharmacogenomics) is offered by the National Human Genome
Research Institute.

Medical Genetics Summaries (https://www.ncbi.nlm.nih.gov/books/NBK61999/),

provided by the National Center for Biotechnology Information at the National Library of
Medicine, provides information about specific genetic variants and how they can impact
drug responses.

Additional information about pharmacogenetics is available from the Centre for Genetics
Education (https://www.genetics.edu.au/SitePages/Pharmacogenomics.aspx) as well as
Genes In Life (http://www.genesinlife.org/testing-services/testing-genetic-conditions/pha

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 211

rmacogenomic-testing).

PharmGKB (https://www.pharmgkb.org/) is a pharmacogenomics resource sponsored

by the National Institutes of Health that collects information on human genetic variation
and drug responses.

A list of clinical trials involving pharmacogenomics (https://clinicaltrials.gov/search/term=

pharmacogenomics+OR+pharmacogenetics) is available from ClinicalTrials.gov, a
service of the National Institutes of Health.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 212

 10.4 What are genome editing and CRISPR-Cas9?
Genome editing (also called gene editing) is a group of technologies that give scientists
the ability to change an organism's DNA. These technologies allow genetic material to
be added, removed, or altered at particular locations in the genome. Several
approaches to genome editing have been developed. A well-known one is called
CRISPR-Cas9, which is short for clustered regularly interspaced short palindromic
repeats and CRISPR-associated protein 9. The CRISPR-Cas9 system has generated a
lot of excitement in the scientific community because it is faster, cheaper, more accurate,
and more efficient than other genome editing methods.

CRISPR-Cas9 was adapted from a naturally occurring genome editing system that
bacteria use as an immune defense. When infected with viruses, bacteria capture small
pieces of the viruses' DNA and insert them into their own DNA in a particular pattern to
create segments known as CRISPR arrays. The CRISPR arrays allow the bacteria to "
remember" the viruses (or closely related ones). If the viruses attack again, the bacteria
produce RNA segments from the CRISPR arrays that recognize and attach to specific
regions of the viruses' DNA. The bacteria then use Cas9 or a similar enzyme to cut the
DNA apart, which disables the virus.

Researchers adapted this immune defense system to edit DNA. They create a small
piece of RNA with a short "guide" sequence that attaches (binds) to a specific target
sequence in a cell's DNA, much like the RNA segments bacteria produce from the
CRISPR array. This guide RNA also attaches to the Cas9 enzyme. When introduced
into cells, the guide RNA recognizes the intended DNA sequence, and the Cas9
enzyme cuts the DNA at the targeted location, mirroring the process in bacteria.
Although Cas9 is the enzyme that is used most often, other enzymes (for example Cpf1)
can also be used. Once the DNA is cut, researchers use the cell's own DNA repair
machinery to add or delete pieces of genetic material, or to make changes to the DNA
by replacing an existing segment with a customized DNA sequence.

Genome editing is of great interest in the prevention and treatment of human diseases.
Currently, genome editing is used in cells and animal models in research labs to
understand diseases. Scientists are still working to determine whether this approach is
safe and effective for use in people. It is being explored in research and clinical trials for
a wide variety of diseases, including single-gene disorders such as cystic fibrosis,
hemophilia, and sickle cell disease. It also holds promise for the treatment and
prevention of more complex diseases, such as cancer, heart disease, mental illness,
and human immunodeficiency virus (HIV) infection.

Ethical concerns arise when genome editing, using technologies such as CRISPR-Cas9,
is used to alter human genomes. Most of the changes introduced with genome editing
are limited to somatic cells, which are cells other than egg and sperm cells (germline
cells). These changes are isolated to only certain tissues and are not passed from one
generation to the next. However, changes made to genes in egg or sperm cells or to the
genes of an embryo could be passed to future generations. Germline cell and embryo
genome editing bring up a number of ethical challenges, including whether it would be
permissible to use this technology to enhance normal human traits (such as height or

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 213

intelligence). Based on concerns about ethics and safety, germline cell and embryo
genome editing are currently illegal in the United States and many other countries.

Scientific journal articles for further reading

Ormond KE(1), Mortlock DP(2), Scholes DT(3), Bombard Y(4), Brody LC(5), Faucett
WA(6), Garrison NA(7), Hercher L(8), Isasi R(9), Middleton A(10), Musunuru K(11),
Shriner D(12), Virani A(13), Young CE(3). Human Germline Genome Editing. Am J Hum
Genet. 2017 Aug 3;101(2):167-176. PubMed: 28777929. Free full-text available from
PubMed Central: PMC5544380.

Gupta RM, Musunuru K. Expanding the genetic editing tool kit: ZFNs, TALENs, and
CRISPR-Cas9. J Clin Invest. 2014 Oct;124(10):4154-61. doi: 10.1172/JCI72992. Epub
2014 Oct 1. Review. PubMed: 25271723. Free full-text available from PubMed Central:
PMC4191047.

Hsu PD, Lander ES, Zhang F. Development and applications of CRISPR-Cas9 for
genome engineering. Cell. 2014 Jun 5;157(6):1262-78. doi:10.1016/j.cell.2014.05.010.
Review. PubMed: 24906146. Free full-text available from PubMed Central:
PMC4343198.

Komor AC, Badran AH, Liu DR. CRISPR-Based Technologies for the Manipulation of
Eukaryotic Genomes. Cell. 2017 Apr 20;169(3):559. doi:10.1016/j.cell.2017.04.005.
PubMed: 28431253.

For more information about CRISPR-Cas9 and other genome editing

technologies:
The National Human Genome Research Institute has a series of fact sheets about
genome editing:
• Overview of genome editing (https://www.genome.gov/about-genomics/policy-issue
s/what-is-Genome-Editing)
• How does genome editing work? (https://www.genome.gov/about-genomics/policy-i
ssues/Genome-Editing/How-genome-editing-works)
• How is genome editing used? (https://www.genome.gov/about-genomics/policy-issu
es/Genome-Editing/How-genome-editing-is-used)
• What are the ethical concerns about genome editing? (https://www.genome.gov/ab
out-genomics/policy-issues/Genome-Editing/ethical-concerns)
• What do people think about genome editing? (https://www.genome.gov/about-geno
mics/policy-issues/Genome-Editing/public-opinion)
• What’s happening in genome editing right now? (https://www.genome.gov/about-ge
nomics/policy-issues/Genome-Editing/happening-right-now)

Questions and answers about CRISPR (https://www.broadinstitute.org/what-broad/area

s-focus/project-spotlight/questions-and-answers-about-crispr) are available from the

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 214

Broad Institute.

The Personal Genetics Education Project has a fact sheet, Genetic Modification,
Genome Editing, and CRISPR (https://pged.org/genetic-modification-genome-editing-an
d-crispr/), that provides an introduction to genome editing.

Yourgenome.org (from the Wellcome Genome Campus) provides information for the
public about CRISPR-Cas9 (https://www.yourgenome.org/facts/what-is-crispr-cas9).

A video illustrating how CRISPR-Cas9 works (https://www.youtube.com/watch?v=2pp17

E4E-O8) is available from the McGovern Institute for Brain Research at MIT.

ClinicalTrials.gov has a list of human studies using genome editing (https://clinicaltrials.

gov/ct2/results?cond=&term=CRISPR+OR+genome+editing+OR+gene+editing)
related to various diseases.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 215

 11
Precision Medicine
11.1 What is precision medicine?
According to the Precision Medicine Initiative, precision medicine is "an emerging
approach for disease treatment and prevention that takes into account individual
variability in genes, environment, and lifestyle for each person." This approach will allow
doctors and researchers to predict more accurately which treatment and prevention
strategies for a particular disease will work in which groups of people. It is in contrast to
a one-size-fits-all approach, in which disease treatment and prevention strategies are
developed for the average person, with less consideration for the differences between
individuals.

Although the term "precision medicine" is relatively new, the concept has been a part of
healthcare for many years. For example, a person who needs a blood transfusion is not
given blood from a randomly selected donor; instead, the donor’s blood type is matched
to the recipient to reduce the risk of complications. Although examples can be found in
several areas of medicine, the role of precision medicine in day-to-day healthcare is
relatively limited. Researchers hope that this approach will expand to many areas of
health and healthcare in coming years.

Learn more about precision medicine:

Information is available about precision medicine (https://obamawhitehouse.archives.go
v/blog/2015/01/30/precision-medicine-initiative-data-driven-treatments-unique-your-own
-body) as data-driven treatment.

Information about precision medicine and Genetics Home Reference, the former home
of MedlinePlus Genetics content, is available from the interactive Journal of Medical
Research (i-JMR) article, "Information Needs in the Precision Medicine Era: How
Genetics Home Reference Can Help (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC49
17728/)."(Available through PubMed Central)

The Centers for Disease Control and Prevention covers precision medicine in its
Genomics and Health Impact Blog (https://blogs.cdc.gov/genomics/category/precision-
medicine/).

Information about precision medicine (https://learn.genetics.utah.edu/content/precision/)

is also available from the Genetic Science Learning Center at the University of Utah.

The American Cancer Society provides information about precision medicine in cancer (
https://www.cancer.org/latest-news/personalized-medicine-redefining-cancer-and-its-tre
atment.html).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 216

 11.2 What is the difference between precision medicine and
personalized medicine? What about pharmacogenomics?
There is a lot of overlap between the terms "precision medicine" and "personalized
medicine." According to the National Research Council, "personalized medicine" is an
older term with a meaning similar to "precision medicine." However, there was concern
that the word "personalized" could be misinterpreted to imply that treatments and
preventions are being developed uniquely for each individual; in precision medicine, the
focus is on identifying which approaches will be effective for which patients based on
genetic, environmental, and lifestyle factors. The Council therefore preferred the term "
precision medicine" to "personalized medicine." However, some people still use the two
terms interchangeably.

Pharmacogenomics is a part of precision medicine. Pharmacogenomics is the study of

how genes affect a person’s response to particular drugs. This relatively new field
combines pharmacology (the science of drugs) and genomics (the study of genes and
their functions) to develop effective, safe medications and doses that are tailored to
variations in a person’s genes.

Read more about precision medicine, personalized medicine, and

pharmacogenomics:
A 2011 report from the National Research Council (https://www.ncbi.nlm.nih.gov/books/
NBK91503/) provides a detailed overview of precision medicine, including the reasoning
behind the Council’s preference for the term "precision medicine" over "personalized
medicine."

The National Human Genome Research Institute (NHGRI) has information on

Frequently Asked Questions about pharmacogenomics (https://www.genome.gov/FAQ/
Pharmacogenomics).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 217

 11.3 What is the Precision Medicine Initiative?
The Precision Medicine Initiative is a long-term research endeavor, involving the
National Institutes of Health (NIH) and multiple other research centers, which aims to
understand how a person's genetics, environment, and lifestyle can help determine the
best approach to prevent or treat disease.

The Precision Medicine Initiative has both short-term and long-term goals. The short-
term goals involve expanding precision medicine in the area of cancer research.
Researchers at the National Cancer Institute (NCI) hope to use an increased knowledge
of the genetics and biology of cancer to find new, more effective treatments for various
forms of this disease. The long-term goals of the Precision Medicine Initiative focus on
bringing precision medicine to all areas of health and healthcare on a large scale. To
this end, the NIH has launched a study, known as the All of Us Research Program,
which involves a group (cohort) of at least 1 million volunteers from around the United
States. Participants are providing genetic data, biological samples, and other
information about their health. To encourage open data sharing, participants can access
their health information, as well as research that uses their data, during the study.
Researchers can use these data to study a large range of diseases, with the goals of
better predicting disease risk, understanding how diseases occur, and finding improved
diagnosis and treatment strategies.

Learn more about the Precision Medicine Initiative:

The NIH website about the All of Us Research Program (https://allofus.nih.gov/)
provides information about the goals of and participants in the Precision Medicine
Initiative. A visual overview of the program partners (https://allofus.nih.gov/funding-and-
program-partners) is also available. Additionally, the NIH Precision Medicine Initiative
channel (https://www.youtube.com/channel/UCQId1TfpwPaYiDIGlxEhlkA) on YouTube
includes talks by scientists and others about various aspects of the initiative.

The NCI offers information about the Precision Medicine Initiative and its role in cancer
research (https://www.cancer.gov/news-events/cancer-currents-blog/2015/precision-me
dicine-initiative-2016).

A fact sheet on President Obama’s Precision Medicine Initiative (https://obamawhitehou

se.archives.gov/the-press-office/2015/01/30/fact-sheet-president-obama-s-precision-me
dicine-initiative) explains the project's plans and objectives.

Dr. Francis Collins, former director of the NIH, and Dr. Harold Varmus, former director of
the NCI, wrote more about their vision for the Precision Medicine Initiative (https://www.
nejm.org/doi/full/10.1056/NEJMp1500523) in the New England Journal of Medicine.

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 218

 11.4 What are some potential benefits of precision medicine
and the Precision Medicine Initiative?
Precision medicine holds promise for improving many aspects of health and healthcare.
Some of these benefits will be apparent soon, as the All of Us Research Program
continues and new tools and approaches for managing data are developed. Other
benefits will result from long-term research in precision medicine and may not be
realized for years.

Potential benefits of the Precision Medicine Initiative:

• New approaches for protecting research participants, particularly patients' privacy
and the confidentiality of their data.
• Design of new tools for building, analyzing, and sharing large sets of medical data.
• Improvement of FDA oversight of tests, drugs, and other technologies to support
innovation while ensuring that these products are safe and effective.
• New partnerships of scientists in a wide range of specialties, as well as people from
the patient advocacy community, universities, pharmaceutical companies, and
others.
• Opportunity for a million people to contribute to the advancement of scientific
research.

Potential long-term benefits of research in precision medicine:

• Wider ability of doctors to use patients' genetic and other molecular information as
part of routine medical care.
• Improved ability to predict which treatments will work best for specific patients.
• Better understanding of the underlying mechanisms by which various diseases
occur.
• Improved approaches to preventing, diagnosing, and treating a wide range of
diseases.
• Better integration of electronic health records (EHRs) in patient care, which will
allow doctors and researchers to access medical data more easily.

Read more about the promise of precision medicine and the Precision
Medicine Initiative:
Dr. Francis Collins, former director of the NIH, and Dr. Harold Varmus, former director of
the NCI, wrote about their vision for the Precision Medicine Initiative (https://www.nejm.
org/doi/full/10.1056/NEJMp1500523) in the New England Journal of Medicine. Dr.
Collins also gave a talk about his vision (https://www.youtube.com/watch?v=ObBYk0M
OuDM) for the project, which is available on the NIH Precision Medicine Initiative
channel (https://www.youtube.com/channel/UCQId1TfpwPaYiDIGlxEhlkA) on YouTube.

Examples are available of how precision medicine is helping Americans (https://obama

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 219

whitehouse.archives.gov/blog/2015/01/29/precision-medicine-already-working-cure-ameri
cans-these-are-their-stories). Other examples are available from the Genetic Science
Learning Center at the University of Utah (learn.genetics.utah.edu/content/precision/acti
on/).

Data about participants of the All of Us Research Program can be viewed on their
Research Hub (https://www.researchallofus.org/).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 220

 11.5 What are some of the challenges facing precision
medicine and the Precision Medicine Initiative?
Precision medicine is a growing field. Many of the technologies that are needed to meet
the goals of the Precision Medicine Initiative have only recently been developed. For
example, researchers needed to standardize the collection of clinic and hospital data
from more than 1 million volunteers around the country. They also needed databases to
store large amounts of patient data efficiently.

The Precision Medicine Initiative also raises ethical, social, and legal issues. It is critical
to protect participants’ privacy and the confidentiality of their personal and health
information. Participants need to understand the risks and benefits of participating in
research, which means researchers must have a rigorous process of informed consent.

Cost is also an issue with precision medicine. The Precision Medicine Initiative itself will
cost many millions of dollars in federal funding, and the ongoing initiative will require
Congress to approve funding over multiple years. Technologies such as sequencing
large amounts of DNA are expensive to carry out (although the cost of sequencing is
decreasing). Additionally, drugs that are developed to treat conditions based on
molecular or genetic variations are likely to be expensive. Reimbursement from third-
party payers (such as private insurance companies) for these targeted drugs is also
likely to become an issue.

If precision medicine approaches are to become part of routine healthcare, doctors and
other healthcare providers will need to know more about molecular genetics and
biochemistry. They will increasingly need to interpret the results of genetic tests,
understand how that information is relevant to treatment or prevention approaches, and
convey this knowledge to patients.

Learn more about challenges related to precision medicine:

The NIH Precision Medicine Initiative channel on YouTube (https://www.youtube.com/ch
annel/UCQId1TfpwPaYiDIGlxEhlkA) offers videos of talks by leading experts on various
aspects of the project, including issues related to data collection and sharing, storing
data in electronic health records, and participant protection.

HealthIT.gov describes the technology needs for Precision Medicine Initiative (//https://w
ww.healthit.gov/buzz-blog/precision-medicine/health-it-advances-precision-medicine)
and advances that have been made.

The Precision Medicine Initiative has information about its Privacy and Trust Principles (
https://allofus.nih.gov/protecting-data-and-privacy/precision-medicine-initiative-privacy-a
nd-trust-principles) and Data Security Policy Principles and Framework (https://allofus.ni
h.gov/protecting-data-and-privacy/precision-medicine-initiative-data-security-policy-princ
iples-and-framework-overview).

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 221