1. Lecture 2 Mode of Inheritance
Medical Genetics
Lecture 2 Mode of Inheritance

2. Objectives To know various patterns of inheritance
To know the classification of autosomal inheritance, with clinical examples
To be able to use the Punnet square
To understand the sex-linked mode of inheritance, with clinical examples
To understand the nature of inheritance of mitochondrial genetic disorders.

3. Single Gene Disorders May be: - Autosomal - Sex linked:
Y- linked , holanderic, hemizygote
X- linked , dominant or recessive

4. Modes of Inheritance of Single gene Disorders
Autosomal
Sex Linked
Recessive
Dominant
Y Linked
X Linked
Abnormal
homozygous
Recessive
Dominant
Normal
homozygous
Heterozygous
Normal
Abnormal

5. Autosomal Inheritance

6. 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
homozygous
Normal
homozygous
Heterozygous

7. 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

8. Examples of Autosomal dominant disorders
Familial hypercholesterolemia (LDLR deficiency)
Von Willebrand disease
Adult polycystic kidney disease
Huntington disease
Myotonic dystrophy
Acute intermittent porphyria
Neurofibromatosis type 1
Marfan syndrome

9. 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

10. Punnet Square; for AD inheritance
(Heteroz.) Affected
Mother
Normal
Father D d dD dd
50% Normal
50% Affected
(Heteroz.) Affected
Mother D d DD dD dd
(Heteroz.)
Affected
Father
25% Normal
75% Affected

11. 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.

12. 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 AA Aa aa

13. (2) One Parent Heterozygous:
Male
Female % Off springs normal but carrier “Heterozygous”
50% Normal
_________________________________________________________________________ (3) If one Parent Homozygous:
100% offsprings carriers.
Female A a AA Aa A a Aa

14. Family tree of an Autosomal recessive disorder
Sickle cell disease (SS)
A family with sickle cell disease -Phenotype
Hb Electrophoresis
AA AS SS

15. Examples of Autosomal Recessive Disorders
Disease
Approximate Frequency/1000
Cystic fibrosis
0.5
Recessive Mental retardation
Congenital deafness
0.2
Phenyketonuria
0.1
Sickle cell anaemia
0.1-5
-Thalassaemia
Recessive blindness
Spinal muscular atrophy
Mucopolysaccharidosis

16. Sex-Linked Inheritance

17. 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.
Recessive
X-Linked
Sex – linked
inheritance
Dominant
Y- Linked

18. Y – Linked Inheritance

19. - 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* XX
XY*

20. X – Linked Inheritance
>1400 genes are located on X chromosome (~40% of them are thought to be associated with disease phenotypes)

21. 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

22. - 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.

23. 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
All daughters carriers “not affected, All sons are normal X X*
X*X Y XY

24. (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
XX* XX Y
X * Y XY

25. 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.

26. G6PD Deficiency Prevalence & Heterozygote advantage:
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.

27. 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.

28. 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.

29. ** 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:
50% sons and 50% daughters are affected % of either sex normal.
Contd. X X*
X*X Y XY X* X
XX* XX Y
X*Y XY

30. (3) Affected female (homozygous) and normal male:
OVA
All children affected..
Sperm X* X
X*X
XX* Y
X*Y

31. 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:

32. Fragile X Syndrome FMR1 Mutation The leading inherited form of mental retardation X-linked
Cytogenetic marker on the X Xq27.3 “a fragile site” in which the chromatin fails to condense properly during mitosis
Medicineworld.org: The Fragile X Mental Retardation

33. Mitochondrial Inheritance

35. 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.

36. Example of Mitochondrial Disorders Lebers hereditary optic neuropathy
(LHON)
Rapid Optic nerve death  blindness in young adult life

37. 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.