Medical Genetics

1. Medical Genetics 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 , holandric, hemizygote X- linked , dominant or recessive holandric = from father to son only

4. Modes of Inheritance of Single gene Disorders Autosomal Sex Linked Y Linked Recessive Dominant 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. Learning about Porphyria http://www.genome.gov/19016728

10. Punnet Square; for AD inheritance (Heteroz.) Affected Mother Normal Father 50% Normal 50% Affected (Heteroz.) Affected Mother (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. 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 1Making 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 Both Parents Heterozygous: 25% offspring affected Homozygous”50% Trait “Heterozygous normal but carrier”25% Normal

13. Punnett squareshowing autosomal recessive inheritance: (1) Both Parents Heterozygous: 25% offspring affected Homozygous” 50% Trait “Heterozygous normal but carrier” 25% Normal Contd.

14. (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

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

16. Examples of Autosomal Recessive Disorders

17. Sex-Linked Inheritance

18. 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

19. Y – Linked Inheritance

20. - 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 areHemizygous, the condition exhibits itself whether dominant or recessive. male Female

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

22. X-linked inheritance in male & female XH is the normal allele, Xh is the mutant allele

23. - 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.

24. 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

25. (2) Carrier female, normal male: Ova 50% sons affected, 50% daughters carriers, Sperm (3) Homozygous female, normal male: - All daughters carriers. - All sons affected.

26. 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.

27. G6PD DeficiencyPrevalence & 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.

28. G6PD DeficiencyInheritance 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.

29. 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.

30. ** 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.

31. (3) Affected female (homozygous) and normal male: OVA All children affected.. Sperm

32. X-linked dominant disordere.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)

33. Fragile X SyndromeFMR1 MutationThe leading inherited form of mental retardationX-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

34. Mitochondrial Inheritance

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

36. 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.

37. 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

38. 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.