Medical Genetics

Lecture 2Mode of Inheritance

Objectives

1. To know various patterns of inheritance2. To know the classification of autosomal

inheritance, with clinical examples3. To be able to use the Punnet square4. To understand the sex-linked mode of inheritance,

with clinical examples5. 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

Sex Linked

X LinkedDominantRecessive

Autosomal

Y Linked

Recessive DominantNormal

homozygousHeterozygous

Abnormalhomozygous

Normal

Abnormal

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.

Autosomal Inheritance

Normalhomozygous

HeterozygousAbnormal

homozygous

- 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.

Autosomal Dominant Inheritance

Normal male

Normal female

Disease male

Disease female

Examples of Autosomal dominant disorders

•Familial hypercholesterolemia (LDLR deficiency)Familial hypercholesterolemia (LDLR deficiency)

•Von Willebrand disease

•Adult polycystic kidney diseaseAdult polycystic kidney disease

•Huntington disease

•Myotonic dystrophy

•Acute intermittent porphyriaAcute intermittent porphyria

•Huntington disease

•Neurofibromatosis type 1

•Marfan syndrome

http://www.genome.gov/19016728 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

D d

D DD dD

d dD dd

(Heteroz.) Affected Mother

(Heteroz.)AffectedFather

D d

d dD dd

d

dD dd

(Heteroz.) Affected

Mother

Normal

Father

Punnet Square; for AD inheritance

50% Normal50% Affected

25% Normal75% Affected

- 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.

Autosomal Recessive Inheritance

Punnett square showing autosomal recessive inheritance:

(1) Both Parents Heterozygous:

25% offspring affected Homozygous”

50% Trait “Heterozygous normal but carrier”

25% Normal

Contd.

A a

A AA Aa

a Aa aa

(2) One Parent Heterozygous:

Male

Female 50% Off springs normal but carrier “Heterozygous”

50% Normal

_________________________________________________________________________(3) If one Parent Homozygous:

Male

100% offsprings carriers.

Female

A a

A AA Aa

A AA Aa

A A

a Aa Aa

a Aa Aa

Family tree of an Autosomal recessive disorderSickle cell disease (SS)

A family with sickle cell disease -Phenotype

AA AS SS

Hb Electrophoresis

Disease Approximate Frequency/1000

Cystic fibrosisCystic fibrosis 0.5

Recessive Mental retardation 0.5

Congenital deafness 0.2

PhenyketonuriaPhenyketonuria 0.1

Sickle cell anaemiaSickle cell anaemia 0.1-5

-Thalassaemia-Thalassaemia 0.1-5

Recessive blindness 0.1

Spinal muscular atrophy 0.1

MucopolysaccharidosisMucopolysaccharidosis 0.1

Examples of Autosomal Recessive Disorders

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.

Sex – Linked Inheritance

Sex – linked inheritance

X-Linked

Dominant

Recessive

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

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 & femaleGenotype 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.

- These disorders may be : recessive or dominant.

- 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

All daughters carriers “not affected, All sons are normal

X X

X* X*X X*X

Y XY XY

X – Linked Recessive Inheritance

(2) Carrier female, normal male:

Ova

50% sons affected,

50% daughters carriers,

Sperm

(3) Homozygous female, normal male:- All daughters carriers.- All sons affected.

X* X

X XX* XX

Y X * Y XY

- 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.

X - Linked Recessive Disorders

•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 DeficiencyPrevalence & Heterozygote advantage:

•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.

G6PD DeficiencyInheritance Risk:

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.

Sperm

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

OVA

50% sons and 50% daughters are affected. 50% of either sex normal.

Sperm

Contd.

X X

X* X*X X*X

Y XY XY

X* X

X XX* XX

Y X*Y XY

(3) Affected female (homozygous) and normal male:

OVA

All children affected..

Sperm

X* X*

X X*X XX*

Y X*Y X*Y

X-linked dominant disordere.g. Incontinentia pigmenti (IP)

Normal male

Normal female

Disease male

Disease female

Lethal in males during the prenatal period

National Institute of Neurological Disorders and Stroke:http://www.ninds.nih.gov/disorders/incontinentia_pigmenti/incontinentia_pigmenti.htm

Pedigree pattern

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)

Fragile X SyndromeFMR1 Mutation

The leading inherited form of mental retardationX-linked

Medicineworld.org: The Fragile X Mental Retardation

Cytogenetic marker on the X chromosome @ Xq27.3 “a fragile site” in which the chromatin fails to condense properly during mitosis

Mitochondrial Inheritance

http://ghr.nlm.nih.gov/chromosome=MT

* The defective gene is present on themitochondrial 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.

Mitochondrial Disorders

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.