Medical Genetics
Lecture 2
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 , holanderic, hemizygote
X- linked , dominant or recessive
Modes of Inheritance of Single gene Disorders
Autosomal
Recessive
Sex Linked
Dominant
Y Linked
X Linked
Abnormal
homozygous
Recessive
Normal
homozygous
Heterozygous
Normal
Abnormal
Dominant
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.
Normal
homozygous
Heterozygous
Abnormal
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 half 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
•Adult polycystic kidney disease
•Huntington disease
•Myotonic dystrophy
•Acute intermittent porphyria
•Huntington disease
•Neurofibromatosis type 1
•Marfan syndrome
Learning about Porphyria
http://www.genome.gov/19016728
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
Normal
d
d
dD
dd
d
dD
dd
Father
(Heteroz.) Affected
50% Normal
50% Affected
Mother
(Heteroz.)
Affected
Father
D
d
D
DD
dD
d
dD
dd
25% Normal
75% Affected
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.
Punnett square showing autosomal recessive inheritance:
(1) Both Parents Heterozygous:
25% offspring affected Homozygous”
A
A
a
AA
Aa
50% Trait “Heterozygous normal but
carrier”
25% Normal
a
Aa
aa
Contd.
(2) One Parent Heterozygous:
Male
A
a
A
AA
Aa
A
AA
Aa
Female
50% Off springs normal but carrier
“Heterozygous”
50% Normal
_________________________________________________________________________
(3) If one Parent Homozygous:
Male
A
A
100% offsprings carriers.
Female
a
Aa
Aa
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
Cystic fibrosis
Recessive Mental retardation
Congenital deafness
Phenyketonuria
Sickle cell anaemia
-Thalassaemia
Approximate
Frequency/1000
0.5
0.5
0.2
0.1
0.1-5
0.1-5
Recessive blindness
Spinal muscular atrophy
0.1
0.1
Mucopolysaccharidosis
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
Sex – linked
inheritance
Y- Linked
Recessive
Dominant
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
Female
X
Y*
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
Males
Females
Genotype
Phenotype
XH
Unaffected
Xh
Affected
XH/XH
Homozygous
unaffected
Heterozygous
XH/Xh
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.
- These disorders may be : recessive
or dominant.
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
X*
X*X
X*X
Y
XY
XY
All daughters carriers “not affected,
All sons are normal
(2)
Carrier female, normal male:
Ova
50% sons affected,
Sperm
X*
X
X
XX*
XX
Y
X*Y
XY
50% daughters carriers,
(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 Beeker’s).
- G-6-PD
- Retinitis pigmentosa.
G6PD Deficiency
Prevalence & Heterozygote advantage:
•Prevalence:
• 5-25% in areas endemic to malaria.
• <0.5% in areas nonendemic to malaria.
•Heterozygotes for G6PD deficiency have some
resistance to malaria → survival advantage.
G6PD Deficiency
Inheritance Risk:
•Each son of a mother carrying a G6PD
mutation has a 50% chance of being affected.
•Each daughter of a mother carrying a G6PD
mutation has a 50% chance of being a carrier
•Each daughter of an affected father will be a
carrier
•Each son of an affected father will be
unaffected.
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
X*
X*X
X*X
Y
XY
XY
Sperm
(2) Affected female (heterozygous) and normal male:
OVA
Sperm
X*
X
X
XX*
XX
Y
X*Y
XY
50% sons and 50% daughters are affected.
50% of either sex normal.
Contd.
(3) Affected female (homozygous) and normal male:
OVA
All children affected..
X*
X*
X
X*X
XX*
Y
X*Y
X*Y
Sperm
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 hemizygous males before birth
- Exclusive in females
- Affected female produces affected daughters,
normal daughters, and normal sons in equal
proportions (1:1:1)
National Institute of Neurological Disorders and Stroke:
http://www.ninds.nih.gov/disorders/incontinentia_pigmenti/incontinentia_pigmenti.htm
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=leberhereditaryopticneuropathy
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.