Medical Genetics

Mode of Inheritance
 Objectives
1. To know various patterns of inheritance
2. To know the classification of autosomal
inheritance, with clinical examples
3. To be able to use the Punnet square
4. To understand the sex-linked mode of inheritance,
with clinical examples
5. To understand the nature of inheritance of
mitochondrial genetic disorders.
 Single Gene Disorders
May be: - Autosomal
- Sex linked:
Y- linked , holandric, hemizygote
X- linked , dominant or recessive

holandric = from father to son only

 Modes of Inheritance of Single gene Disorders

Autosomal Sex Linked

Recessive Dominant Y Linked X Linked

Abnormal
homozygous

Recessive Dominant
Normal Heterozygous
homozygous
Normal
Abnormal
Autosomal Inheritance
 Autosomal Inheritance

- This is the inheritance of the gene present on the Autosomes.

Both sexes have equal chance of inheriting the disorder (The

occurrence and transmission of the trait is not affected by sex)

Two types:
Autosomal dominant inheritance, if the gene is dominant.
Autosomal recessive inheritance, if the gene is recessive.

Abnormal
Normal Heterozygous homozygous
homozygous
 Autosomal Dominant Inheritance

- Autosomal dominant inheritance, if the gene is dominant.

- The trait (character, disease) appears in every generation.
- The trait is transmitted by an affected (heterozygous) person
to the children.
- Unaffected persons do not transmit the trait to their children.

Normal male
Normal female
Disease male
Disease female
Examples of Autosomal dominant disorders
•Familial hypercholesterolemia (LDLR deficiency)
•Von Willebrand disease (disease of clotting)
•Adult polycystic kidney disease
•Huntington disease (brain disorder,
lack of thinking ability )
•Myotonic dystrophy (muscle function disorder)
•Neurofibromatosis type 1
•Marfan syndrome (connective disorder, tall feature
 Learning about Porphyria

        Dad and 2 children have not got porphyria

        Mum and 2 children have acute porphyria and are at
risk of developing an acute attack
 Punnet Square; for AD inheritance (Heteroz.) Affected
Mother
D d

Normal d dD dd
Father
d dD dd

50% Normal
50% Affected
(Heteroz.) Affected
Mother
D d

(Heteroz.) D DD dD 25% Normal

Affected 75% Affected
Father d dD dd
 Autosomal Recessive Inheritance

- The trait (character, disease) is recessive.

- The trait expresses itself only in homozygous state.

- Unaffected persons (heterozygotes) may have affected

childrens (if the other parent is heterozygote) .

- The parents of the affected child maybe related

(consanguineous).

- Males and female are equally affected.

A Punnett square simulates two organisms reproducing sexually,
examining just one of the many genes that get passed on. The
completed square shows every possible way the offspring could inherit
this gene, and what the chances are for each result. Making Punnett
squares is a good way to get started understanding the fundamental
concepts of genetics.
Part 1 Making a Punnett Square
Draw a 2 x 2 grid. ...
Name the alleles involved. ...
Check the parents' genotypes. ...
Label the rows with one parent's genotype. ...
Label the columns with the other parent's genotype. ...
Have each box inherit letters from its row and column. ...
Interpret the Punnett square. ...
Describe the phenotype.
autosomal recessive inheritance
A a Both Parents Heterozygous:
50% offspring affected
A AA Aa Homozygous” 50% Trait
“Heterozygous normal
a Aa aa
 (2) One Parent Heterozygous:
Male

A a
Female 50% Off springs normal
“Heterozygous”
A AA Aa
50% Normal

A AA Aa

_________________________________________________________________________ (3)
If one Parent Homozygous:
Male
A A

a Aa Aa 100% offsprings carriers.

Female
a Aa Aa
Family tree of an Autosomal recessive disorder
Sickle cell disease (SS)

A family with sickle cell disease -Phenotype

Hb Electrophoresis
AA AS SS
 Examples of Autosomal Recessive Disorders

Disease Approximate
Frequency/1000
Cystic fibrosis 0.5
Recessive Mental retardation 0.5
Congenital deafness 0.2
Phenyketonuria 0.1
Sickle cell anaemia 0.1-5
-Thalassaemia 0.1-5
Recessive blindness 0.1
Spinal muscular atrophy 0.1
Sex-Linked Inheritance
 Sex – Linked Inheritance

- This is the inheritance of a gene present on the sex

chromosomes.

- The Inheritance Pattern is different from the

autosomal inheritance.

- Inheritance is different in the males and females.

X-Linked Recessive
Sex – linked
inheritance
Dominant
Y- Linked
Y – Linked Inheritance
- The gene is on the Y chromosomes.

- Shows Holandric inheritance. i.e.

The gene is passed from fathers to sons only.

- Daughters are not affected.
e.g. Hairy ears in India.

- Male are Hemizygous, the condition exhibits itself whether

dominant or recessive.
male

X Y*

Female
X XX XY*

X XX XY*
 X – Linked Inheritance
• >1400 genes are located on X
chromosome (~40% of them are thought
to be associated with disease phenotypes)
X-linked inheritance in male & female
Genotype Phenotype

Males XH Unaffected

Xh Affected

Females XH/XH Homozygous

unaffected
XH/Xh Heterozygous

Xh/Xh Homozygous
affected
XH is the normal allele, Xh is the mutant allele
- The gene is present on the X - chromosome.

- The inheritance follows specific pattern.

- Males have one X chromosome, and are

hemizygous.

- Females have 2 X chromosomes, they may be

homozygous or heterozygous.
 X – Linked Recessive Inheritance

- The incidence of the X-linked disease is higher in male than in

female.
- The trait is passed from an affected man through all his
daughters to half their sons.
- The trait is never transmitted directly from father to sons.
- An affected women has affected sons and carrier daughters.
(1) Normal female, affected male
Ova
X X All daughters carriers “ affected,
All sons are normal
X* X*X X*X

Y XY XY
(2) Carrier female, normal male:

Ova
50% sons affected,
X* X
50% daughters carriers,
X XX* XX
Sperm

Y X*Y XY

(3) Homozygous female, normal male:

- All daughters carriers.
- All sons affected.
X - Linked Recessive Disorders

- Albinism (Ocular).
- Angiokeratoma (Fabry’s disease).
- Chronic granulomutous disease.
- Ectodermal dysphasia (anhidrotic).
- Fragile X syndrome.
- Hemophilia A and B.
- Ichthyosis (steroid sulphatase deficiency).
- Lesch–Nyhan syndrome.
- Menkes’s syndrome.
- Mucopoly Sacchuridosis 11 (Hunter’s
syndrome)
- Muscular dystrophy (Duchenne and Becker’s).
- G-6-PD
- Retinitis pigmentosa.
 X-Linked Dominant Disorders

- The gene is on X Chromosome and is dominant.

- The trait occurs at the same frequency in both males

and females.

- Hemizygous male and heterozygous females express

the disease.
 ** Punnett square showing X – linked dominant type of Inheritance:

(1) Affected male and normal female:

OVA
All daughters affected, all sons
normal. X X
Sperm
X* X*X X*X

Y XY XY

(2) Affected female (heterozygous) and normal male:

OVA
50% sons and 50% daughters are
affected. X* X 50% of either sex
normal.
Sperm X XX* XX

Y X*Y XY
Contd.
 (3) Affected female (homozygous) and normal male:
OVA
All children affected..
X* X*

Sperm

X X*X XX*

Y X*Y X*Y
 X-linked dominant disorder
e.g. Incontinentia pigmenti (IP)

Pedigree pattern
Normal male
Normal female
Disease male
Disease female

Lethal in males during the prenatal period

Lethal in before birth
- females
- Affected female produces affected daughters,
normal daughters, and normal sons in equal
proportions (1:1:1)
 Fragile X Syndrome
FMR1 Mutation
The leading inherited form of mental retardation
X-linked

Cytogenetic marker on the X chromosome @ Xq27.3 “a fragile site” in which the

chromatin fails to condense properly during mitosis

Medicineworld.org: The Fragile X Mental Retardation

Mitochondrial Inheritance
http://ghr.nlm.nih.gov/chromosome=MT
 Mitochondrial Disorders
* The defective gene is present on the
mitochondrial chromosomes.
•Effect generally energy metabolism.
* Effect more those tissues which require
constant supply of energy e.g muscles.
* Shows maternal inheritance:
-affected mothers transmit the disorder
equally to all their children.
-affected fathers do not transmit the
disease to their children.
 Example of Mitochondrial Disorders

Lebers hereditary optic neuropathy

(LHON)
Rapid Optic nerve death  blindness in young adult life

http://ghr.nlm.nih.gov/condition=leberhereditaryopticneuropath
y
 Mitochondrial Inheritance

- Affected females transmit the disease to all their children.

- Affected males have normal children.
- Males cannot transmit the disease as the cytoplasm is inherited
only from the mother, and mitochondria are present in the
cytoplasm.