GENETICS

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 GENETICS

• Genetics is the study of heredity or inheritance.

The study of genetics helps to explain how traits
are passed from parents to their young.
•  Gregor John Mendel - Father of Genetics.

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Body made of organs

Organs made of tissues

Tissue made of cells

Cells contain nucleus

Nucleus contain chromosomes
Chromosome made of DNA  
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 COMPARED TO BOOK….
Book of life  •Two chromosomal sets (Mum &   
Two volumes Dad)
Each volume  23 
chapters •Each set has 23 chromosomes

Each chapter has many  • Each chromosome has many genes
sentences

Each sentence conveys  • Each gene has specific function 
meaning

Sentence has many  • Gene has many codons
words

Words made of  • Codons are three letter word made 
alphabets of A,T,G,C
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 ETIOLOGY OF GENETIC DISORDERS

• Chromosomal
• Single gene
• Mitochondrial
• Multifactorial

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 CHROMOSOMAL DISORDERS

• Damage to chromosomes due to physical or 
chemical disturbances or errors during meiosis.
• Two Types:
1. Chromosome Structure
2. Chromosome Number

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 CHROMOSOME STRUCTURE

1. Deletion – during cell division, especially meiosis, a

piece of the chromosome breaks off, may be an
end piece or a middle piece
2. Inversion – a segment of the chromosome is
turned 180°, same genes but opposite position
3. Duplication – a doubling of a chromosome
segment because of attaching a broken piece form
a homologous chromosome, or by unequal
crossing over.
4. Translocation – movement of a chromosome
segment from one chromosome to a non-
homologous chromosome
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* Translocation is of more clinical importance
SIMPLE TRANSLOCATION             RECIPROCAL TRANSLOCATION

     Robertsonian Translocation
     Chromosomal rearrangement 
that is formed by fusion of the 
whole long arms of 
two acrocentric chromosomes 
(chromosomes with 
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the centromere near the very end)
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 CHROMOSOME NUMBER

1. Monosomy – only one of a particular type of

chromosome (2n -1)
2. Trisomy – having three of a particular type of
chromosome (2n + 1)
3. Polyploidy – having more than two sets of
chromosomes; triploids (3n = 3 of each type of
chromosome), tetraploids (4n = 4 of each type
of chromosome).
n=23 ; 2n=46
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 CLINICAL SCENARIO 1

• 10 day old baby, 
presenting with poor 
suck
• On examination, 
hypotonic, dysmorphic 
facies, single palmer 
crease both hands.
• Diagnosis
• Counseling
• Confirmation

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 FURTHER STEPS

• Diagnosis: Clinical features consistent with Down 
syndrome
• Counseling: Important aspect, discuss with the parents 
the likely condition and the need for confirmatory testing
• Confirmation: FISH (Fluorescent in situ hybridization) for 
chromosome 21 (Reported in 48‐72 hours) and 
karyotyping (reported in 2‐ 3 weeks)
• Need for cytogenetic testing: Down syndrome occurs due 
to non‐dysjunction of chromosome leading to trisomy 21 
or due to unbalanced Robertsonian translocation or 
mosaic pattern with cells with normal chromosome and 
trisomy
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 NON‐DYSJUNCTION OF CHROMOSOME

Failure to move apart during Meiosis I or Meiosis II
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KARYOTYPING REPORT‐DOWN SYNDROME

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 CLINICAL SCENARIO 2

• 1.8 kg male baby born at term had a fisted hand 
rocker bottom feet, hypospadias, loud systolic 
murmur & developed respiratory distress in a few 
hrs of life  

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EDWARD SYNDROME

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KARYOTYPING REPORT CONFIRMS TRISOMY 18

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 CLINICAL SCENARIO 3

• 12 year old girl was brought by mother for primary 
amenorrhea. She was short statured. CVS 
examination showed systolic murmur in the left 
upper sternal border. She had hyperconvex nails 
with café‐au‐lait spots.
• Her bone age is normal
• Next best investigation to do 

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KARYOTYPING‐ TURNERS SYNDROME

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 CLINICAL SCENARIO 4

• 2 year old boy, presented with developmental delay. 
He had episodes of colic during infancy. Child is very 
friendly and sociable. He had dental abnormality.

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 FACIAL FEATURES                          

Puffy eyes

Small bulbous nose

Long philtrum

Small widely spaced 
teeth

Overhanging lower lip

Small chin

Possum picture
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 DIAGNOSIS

• Diagnosis of Williams syndrome suspected
• Confirmation of diagnosis by FISH (Fluorescent in situ 
hybridization) testing
• Microdeletion where segment of chromosome gets 
deleted which cannot be picked up by routine 
karyotyping
• Investigation of choice‐ FISH for Microdeletion 
analysis for locus 7q 11.23

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 FISH ASSAY

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 SINGLE GENE DISORDERS

 Occurs due to genetic mutation – either Point mutation 
(change in single nucleotide) or Frame shift mutations
 Single gene disorders
 Autosomal dominant
 Autosomal recessive
 X‐Linked dominant
 X‐Linked recessive
 Y‐Linked

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 AUTOSOMAL DOMINANT

50% risk of offspring of 
affected father/mother 
being affected

Independent of sex

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 AUTOSOMAL DOMINANT

E.g.: Huntington’s Disease, Achondroplasia, 
Neurofibromatosis
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 AUTOSOMAL RECESSIVE

Carrier parents have 25% 
risk of having affected 
offspring
50% ‐ carrier offspring
25% ‐ normal

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 AUTOSOMAL RECESSIVE

e.g.  Majority of inborn errors of 
metabolism Gauchers disease, Morquio 
syndrome  
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 X‐LINKED DOMINANT
Female with one mutant 
allele will be affected. 
Affected male – all 
daughters affected, no sons 
affected.
50% of sons and 50% of 
daughters of affected 
mother will be affected.
Hence, resembles 
autosomal dominant. 
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 X‐LINKED DOMINANT

E.g.: Fragile X, Incontinentia pigmenti
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 X‐LINKED RECESSIVE

 50% of sons of carrier female to

be affected.
 50% of daughters of carrier
females to be carriers.
 Affected males do not transmit to
sons.
 All daughters of affected male to
be carriers.

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 X‐LINKED RECESSIVE

E.g.: Hemophilia, Duchenne muscular dystrophy

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 Y-LINKED

Only male to male transmission 
E.g. Male infertility
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 POLYMORPHISM

• Polymorphism is a genetic variant that appears in at 
least 1% of a population.
•  Example : ABO blood groups

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 DIAGNOSIS OF SINGLE GENE DISORDER

• Molecular analysis for the gene
• PCR analysis (Polymerase Chain Reaction)/ Sanger 
sequencing
• Newer technique where multiple genes are 
responsible for same phenotype‐ Next gen 
sequencing 
• If unknown mutation – Whole exome sequencing
• Importance of molecular diagnosis: Prognostication 
and for prenatal diagnosis during next pregnancy

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 MITOCHONDRIAL INHERITENCE
Only females can transmit
the trait to offspring ; Affected
female will transmit disease to
male and female children alike.
Mother with a small no. of
mtDNA mutated unaffected. If
mitochondria with mutated
mtDNA replicate more in the
zygote , the baby can become
affected.
e.g.. Electron transport defects, Pyruvate  Hence disease status depends
dehydrogenase deficiency
on mutated mtDNA load;
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Presents as energy failure
 MULTIFACTORIAL
In multifactorial conditions a
genetic mutation may
predispose an individual to
a disease.
Other genetic and
environmental factors
Genetic Environmental
contribute to whether or not factors factors
the disease develops.
 Example:
• Skin color ‐ many genes 
and UV exposure
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DISORDER FEATURES DIAGNOSTIC 
TESTING
Chromosomal Dysmorphism,  Cytogenetics 
multisystem  (Karyotyping and 
involvement FISH)
Microdeletion Dysmorphism,  FISH Fluorescent in 
multisystem  situ hybridization
involvement
Single gene  Pedigree – Family  Molecular testing 
disorder history Specific findings PCR (Polymerase 
chain reaction)
Mitochondrial Pedigree – Family  Genome 
history Specific findings sequencing
Multifactorial History and findings Individualised
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 TAKE HOME MESSAGE

• Genetic disorders include 
 Chromosomal disorders (e.g. Down syndrome),
 Microdeletion disorders (e.g. William syndrome),
 Single gene disorders‐ Autosomal dominant, Autosomal 
recessive, X‐ linked dominant, X‐ linked recessive 
 Mitochondrial and multifactorial inheritance
• Definitive diagnosis by cytogenetics or molecular 
testing are essential for prognosticating and for 
prenatal diagnosis during subsequent pregnancies.

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THANK YOU

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