Class 2: Pedigree, Patterns of Inheritance
Pedigrees are used to analyze the pattern of inheritance of a particular trait/genetic
disorders throughout a family. Pedigrees show the presence or absence of
trait/genetic disorder as it relates to the relationship among parents, offspring, and
siblings.
Each pedigree chart represents all of the available information about the
inheritance of a single trait (most often a disease) within a family. The pedigree
chart is therefore drawn using factual information, but there is always some
possibility of errors in this information, especially when relying on family
members’ recollections or even clinical diagnosis. A pedigree may be drawn when
trying to determine the nature of a newly discovered disease, or when an individual
with a family history of a disease wants to know the probability of passing the
disease on to their children.
Pedigrees represent family members and relationships using standardized symbols.
Pedigree analysis is therefore an important tool in both basic research and genetic
counseling.The affected individual that brings the family to the attention of a
geneticist is called the Proband (or propositus).
Each generation is depicted with roman numbers and individuals within a
generation by a numerical
Patterns of Inheritance:
Inheritance patterns trace the transmission of genetically encoded traits, conditions
or diseases to the offspring.
Reason for studying the pattern of inheritance is to enable advice to be given to
members of family regarding the likelihood of their developing it or passing it on
to their children.
Classified as:
Patterns of
Inheritance
Single Gene/
Multifactorial Mitochondrial
Mendelian
Single gene disorders:
Genetic conditions caused by a mutation in a single gene. It is also referred to as
Mendelian inheritance, More than 16,000 traits and disorders have been identified.
A trait or disorder determined by a gene on autosome is called autosomal
inheritance, whereas a trait or disorder determined by gene on sex chromosome is
called sex-linked inheritance.
Autosomal inheritance is classified into Autosomal Dominant and Autosomal
Recessive inheritance.
Autosomal Dominant Inheritance
1. Only one copy of the disease allele is necessary for an individual to express the
phenotype i.e., it is expressed in heterozygous condition [Individual has one
abnormal and one normal allele].
2. Males and females are equally affected.
3. With each of the pregnancy [one parent affected] , there is 1 in 2 chance [50%]
the offspring will inherit the disease
4. All affected individuals will have at least one parent who carries the disease
allele, except in case of a new mutation.
5. Autosomal dominant inheritance is called as Vertical transmission because of
the transmission from parent to offspring. It can be traced through many
generations.
Examples: Achondroplasia, Osteogenesis Imperfecta, Huntington’s disease,
Marfans syndrome, Polycystic kidney
Achondroplasia
Achondroplasia is a disorder of bone growth that prevents the changing of cartilage
(particularly in the long bones of the arms and legs) to bone. It is caused
by mutations in the FGFR3 gene. Inheritance is autosomal dominant.
Clinical Features:
Dwarfism
Limited range of motion at the elbows
Macrocephaly
Prominent forehead
Small fingers and toes
Trident hands
Apnea
Recurrent ear infections,
Lordosis
More serious problems - Spinal stenosis, Hydrocephalus
Autosomal Recessive Inheritance
1. Two copies (Homozygous state) of the disease allele are required for an
individual to be susceptible to expressing the phenotype.
2. Individuals heterozygous for mutant allele and show no abnormal features are
called carriers.
3. Males and females are affected equally.
4. Affected individuals are seen in single generation (brothers and sisters) -
horizontal transmission.
5. With each pregnancy of carrier parents the following possibilities are seen:
One in four (25%) chance the offspring will inherit two copies of the
disease allele and will therefore have the phenotype.
One in two (50%) chance the offspring will inherit one copy of the
disease allele and will be a carrier.
One in four (25%) chance the offspring will inherit no copies of the
disease allele and will not express the phenotype or be a carrier. This
individual would not be at risk for passing the disorder on to his/her
offspring.
Examples: Sickle cell anemia, Cystic fibrosis, Phenylketonuria, Tay-Sachs,
Hemochromatosis, Galactosemia
Sickle Cell Anemia
It is an inherited form of anemia. It is a condition in which there aren't enough
healthy red blood cells to carry adequate oxygen throughout your body.
Normally, red blood cells are flexible and round, moving easily through your blood
vessels. In sickle cell anemia, the red blood cells become rigid and sticky and are
shaped like sickles. These irregularly shaped cells can get stuck in small blood
vessels, which can slow or block blood flow and oxygen to parts of the body. It is
an autosomal recessive inheritance.
Clinical Features:
Anemia
Episodes of pain
Painful swelling of hands and feet
Frequent infections
Delayed growth
Vision problems
Complications: Stroke, Acute chest syndrome, Pulmonary hypertension, Organ
damage, Blindness, Leg ulcers
Cystic Fibrosis
It is a hereditary disease that affects the lungs and digestive system. The body
produces thick and sticky mucus that can clog the lungs and obstruct the pancreas.
It is serious, with potentially life threatening consequences. The most common
cause of death in the affected individuals is Respiratory failure. It is an autosomal
recessive inheritance.
Clinical Symptoms:
Salty – tasting skin
Persistent coughing
Shortness of breath
Wheezing
Poor weight gain
Greasy, bulky stools
Nasal polyps
Severe constipation
Sex – Linked inheritance is classified into X – Linked Dominant and X – Linked
Recessive and Y- Linked inheritance.
X- Linked Dominant Inheritance
1. The disorders manifests in heterozygous form in females as well as in the male,
with the mutant allele on his single X chromosome [Hemizygous].
2. When a female is affected, each progeny will have 1 in 2 (50%) chance for the
progeny to inherit the disease allele
3. Affected male transmits to all his daughters but none to his sons.
4. Both males and females can be affected, although males may be more severely
affected because they only carry one copy of genes found on the X
chromosome. Some X-linked dominant disorders are lethal in males.
Examples: Vitamin D-resistant rickets, Incontinentia pigmenti, Rett Syndrome,
Fragile– X syndrome, Alport’s syndrome.
Vitamin D – Resistant Rickets
It is a disorder characterized by hypophosphatemia, defective intestinal absorption
of calcium and rickets. It is a X-linked dominant inheritance.
Clinical Symptoms:
Bone pain
Fractures
Growth abnormalities
Osteoarthritis
X- Linked Recessive Inheritance
1. X-LR trait usually manifests in males i.e., in Hemizygous condition than in
females.
2. It is transmitted by healthy heterozygous female carriers.
3. Affected male transmits to all his daughters - obligate carriers, with a
consequent risk to male grandchildren through daughters. This type of pedigree
is referred to as a ‘diagonal or a knight’s move’ pattern of transmission. None
of the sons will be affected.
4. For a carrier female, with each pregnancy there is a one in two (50%) chance
her sons will inherit the disease allele and a one in two (50%) chance her
daughters will be carriers.
5. Women are affected when they have two copies of the disease allele. All of
their sons will be affected, and all of their daughters will be unaffected carriers.
Examples: Hemophilia, DMD (Duchenne Muscular Dystrophy), Becker’s
Muscular Dystrophy, Color blindness, Ocular Albinism.
Hemophilia
It is a disorder in which blood doesn't clot normally because of the lack of blood-
clotting proteins (clotting factors). People with hemophilia produce lower amounts
of either Factor VIII or Factor IX.
There are two major types of hemophilia, type A and type B.
In hemophilia A, there is a lack of clotting factor VIII and in hemophilia B, there is
a lack of clotting factor IX. Both A and B can be mild, moderate, or severe,
depending on the amount of clotting factor that is in the blood. It is a X-linked
recessive inheritance.
Clinical Symptoms:
1. Excessive bleeding.
2. Bleeding can occur externally or internally. Excessive internal bleeding
includes blood in the urine or stools, and large, deep bruises.
3. Any wound, cut, bite, or dental injury can lead to excessive external bleeding
4. Spontaneous nosebleeds are common.
5. Bleeding can also happen within joints, like knees and elbows, causing them to
become swollen, hot to the touch, and painful to move.
6. A person with hemophilia may experience internal bleeding in the brain
following a bump on the head. Symptoms of brain bleeding can
include headaches, vomiting, lethargy, behavioral changes, clumsiness, vision
problems, paralysis, and seizures.
Duchenne Muscular Dystrophy
It is a genetic disorder characterized by progressive muscle degeneration and
weakness due to the alterations of a protein called dystrophin that helps keep
muscle cells intact.
Clinical Symptoms:
1. Muscle weakness is the principal symptom of DMD. It can begin as early as age
2 or 3, first affecting the proximal muscles and later affecting the distal limb
muscles.
2. Lower external muscles are affected before the upper external muscles.
3. Affected individual might have difficulty jumping, running, and walking.
4. Enlargement of the calves
5. Waddling gait
6. Lumbar lordosis
7. Later stages - heart and respiratory muscles are affected
8. Progressive weakness and scoliosis result in impaired pulmonary function,
leading to acute respiratory failure.
Y-linked inheritance / Holandric inheritance:
Y- Linked or holandric inheritance implies that only males are affected. Affected
male transmits Y –linked trait to all his sons, but none to the daughters.
Examples: Male Infertility, Swyer syndrome
Multifactorial Inheritance
The disorders involved is claimed to be controlled by many genes “Polygenic”
with small additive effects, in association with the environmental factors and
lifestyle is called multifactorial and polygenic disorders.
It does not follow any clear pattern of inheritance and does not show any
identifiable abnormality of the chromosome morphology.
Multifactorial inheritance has been proposed to account for the common congenital
malformations and acquired disorders.
Examples: Congenital malformations – Cleft lip/ palate, Neural tube defects
Acquired diseases – Asthma, Hypertension, Diabetes Mellitus, Epilepsy,
Schizophrenia, Glaucoma
Mitochondrial Inheritance
It is also known as matrilineal / cytoplasmic inheritance.
Both males and females are affected but only females transmit the disease, this is
because the developing embryo derives mitochondrial DNA from the ovum.
Primary function of mitochondria is conversion of molecules into usable energy.
Thus, many diseases transmitted by mitochondrial inheritance affect organs with
high energy use such as the heart, skeletal muscle, liver and kidney.
Examples: Leber’s hereditary optic atrophy, Diabetes with deafness, Hypertrophic
Cardiomyopathy, Leigh syndrome, MELAS [Mitochondrial myopathy,
encephalomyopathy, lactic acidosis, stroke like symptoms], Myoclonic epilepsy
Autosomal Dominant Inheritance
Autosomal Recessive Inheritance
X- Linked Dominant Inheritance
X- Linked Recessive Inheritance
