2. LECTURE - 2 Learning objectives Genetic disease Genetic disease Classification Classification Mutations Mutations Mendelian disorders Mendelian disorders

3. 3 GENETIC DISEASE Encountered - tip of iceberg Encountered - tip of iceberg 50% spontaneous abortuses - chromosomal abnormality 50% spontaneous abortuses - chromosomal abnormality 1% newborns have gross chromosomal abnormality 1% newborns have gross chromosomal abnormality 5% < 25 yr develop dis. with significant genetic defect 5% < 25 yr develop dis. with significant genetic defect

4. 4 GENETIC DISORDERS Mendelian disorders: mutations in single gene of large effect: autosomal dominant/recessive, X-linked disorders Mendelian disorders: mutations in single gene of large effect: autosomal dominant/recessive, X-linked disorders Multifactorial (polygenic) inheritance Multifactorial (polygenic) inheritance Single gene disorders with non-classic inheritance, mutation of mtDNA genes Single gene disorders with non-classic inheritance, mutation of mtDNA genes Chromosomal / cytogenetic disorders Chromosomal / cytogenetic disorders Classification

5. 5 MENDELIAN DISORDERS Result of expressed mutations in single gene of large effect Result of expressed mutations in single gene of large effect About 4500 disorders discovered About 4500 disorders discovered All carrier of 5-8 deleterious genes All carrier of 5-8 deleterious genes Mostly recessive, 80-85% familial Mostly recessive, 80-85% familial Other de novo mutations may occur Other de novo mutations may occur Many types of Mendelian disorders Many types of Mendelian disorders

7. 7 MUTATION Permanent change in DNA 1. Genomic mutation : loss or gain of whole chromosome 2. Chromosomal mutations : visible structural changes 3. Gene mutations : addition/ deletion, frame shift

8. 8 GENE MUTATIONS Point mutations in coding sequences Point mutations in coding sequences  Missense : sickle cell anemia  Nonsense : thalassaemia Mutations noncoding sequence - effect introns, hereditary hemolytic anemias Mutations noncoding sequence - effect introns, hereditary hemolytic anemias Deletion / insertion in coding sequence, not in triplet : frame shift mutations Deletion / insertion in coding sequence, not in triplet : frame shift mutations

9. 9

11. 11 PENETRANCE - % carrying autosomal dominant gene and expressing the trait PENETRANCE - % carrying autosomal dominant gene and expressing the trait EXPRESSIVITY - variable expression of autosomal dominant trait EXPRESSIVITY - variable expression of autosomal dominant trait DEFINITIONS

12. 12 AUTOSOMAL DOMINANT DISORDERS Generalizations Generalizations Disease appears in each generation Disease appears in each generation equally liable to get/transmit disease equally liable to get/transmit disease Only transmitted by an effected parent Only transmitted by an effected parent Each child - 50% risk of gene / disease Each child - 50% risk of gene / disease Children of unaffected parent not at risk Children of unaffected parent not at risk Mutation in structural/regulatory proteins Mutation in structural/regulatory proteins

13. 13 AUTOSOMAL DOMINANT DISORDERS Exceptions ! Clinical feature modified by reduced penetrance / variable expressivity Clinical feature modified by reduced penetrance / variable expressivity Some patients - no effected parents Some patients - no effected parents Delayed onset in some individuals Delayed onset in some individuals Most patients are heterozygous Most patients are heterozygous Homozygous more serious disease Homozygous more serious disease

15. 15 AUTOSOMAL DOMINANT DISORDERS Nervous - Huntington's dis., tuberous sclerosis, neurofibromatosis Nervous - Huntington's dis., tuberous sclerosis, neurofibromatosis Urinary - polycystic kidney disease Urinary - polycystic kidney disease Haemopoietic - spherocytosis, ww dis. Haemopoietic - spherocytosis, ww dis. Skeletal - Marfan's synd, Ehlers - Danlos, osteogenesis imperfecta, achondroplasia Skeletal - Marfan's synd, Ehlers - Danlos, osteogenesis imperfecta, achondroplasia Metabolic - familial hypercholesterolemia, acute intermittent porphyria Metabolic - familial hypercholesterolemia, acute intermittent porphyria

16. 16 AUTOSOMAL RECESSIVE DISORDERS Un-effected parents – sudden in family Un-effected parents – sudden in family equally likely to have disease equally likely to have disease Consanguinity more common, certain recessive traits more common in isolated groups of the population Consanguinity more common, certain recessive traits more common in isolated groups of the population 25%, 2 / 4 carriers, expression uniform 25%, 2 / 4 carriers, expression uniform Almost all inborn errors of metabolism Almost all inborn errors of metabolism

17. 17

18. 18 AUTOSOMAL RECESSIVE DISORDERS Metabolic - cystic fibrosis, PKU, galactosaemia, lysosomal storage disease, alpha 1-antitrypsin deficiency, Wilson's disease, glycogen storage Metabolic - cystic fibrosis, PKU, galactosaemia, lysosomal storage disease, alpha 1-antitrypsin deficiency, Wilson's disease, glycogen storage Haem - sickle cell anemia, thalassemia Haem - sickle cell anemia, thalassemia Nervous - neurogenic muscular dystrophy, Friedrich's ataxia, spinal muscular atrophy Nervous - neurogenic muscular dystrophy, Friedrich's ataxia, spinal muscular atrophy

19. 19 SEX - LINKED DISORDERS Gonosomes determinant Gonosomes determinant Hetero / homogametic sex Hetero / homogametic sex Birds / reptiles reverse Birds / reptiles reverse Some species hermaphrodite Some species hermaphrodite X-linked : recessive/dominant X-linked : recessive/dominant Y- linked inheritance Y- linked inheritance XX XY

20. 20 X-LINKED RECESSIVE XX INHERITANCE X Y Males clinical dis. ; effected male - all daughters carrier, sons normal; carrier mother - 50% sons affected Males clinical dis. ; effected male - all daughters carrier, sons normal; carrier mother - 50% sons affected No male to male transmission No male to male transmission Disease may skip a generation, rarely disease in females ( Turner syndrome, homozygous female, translocation, Lyon’s effect ) Disease may skip a generation, rarely disease in females ( Turner syndrome, homozygous female, translocation, Lyon’s effect )

21. X-LINKED RECESSIVE GENOTYPE XY GENOTYPE XY XX XX PHENOTYPE XX - Normal female PHENOTYPE XX - Normal female XY - Affected male XY - Affected male XY - Normal male XX- Carrier female XXXX XY XXXY XXYXY

22. 22 X - LINKED RECESSIVE DISORDERS Musculoskeletal - Duchenne muscle atrophy Musculoskeletal - Duchenne muscle atrophy Blood - hemophilia A/B, G6PD deficiency Blood - hemophilia A/B, G6PD deficiency Immune – agammaglobulinemia, Wiscot - Aldrich syndrome Immune – agammaglobulinemia, Wiscot - Aldrich syndrome Metabolic - diabetes inspidus, Lesch - Nyhan Metabolic - diabetes inspidus, Lesch - Nyhan Nervous - fragile X-syndrome Nervous - fragile X-syndrome

23. EUROPEAN ROYALTY

24. 24 MULTIFACTORIAL INHERITANCE Combined action of environment / genes Combined action of environment / genes More genes - more severe expression of disease More genes - more severe expression of disease Eye color, height, intelligence Eye color, height, intelligence Bell - shaped distribution Bell - shaped distribution Environmental influences Environmental influences Identical twins ≥ 100% risk Identical twins ≥ 100% risk

25. 25 MULTIFACTORIAL DISORDERS Cleft lip / palate Cleft lip / palate Congenital heart disease Congenital heart disease Coronary heart disease Coronary heart disease Diabetes mellitus Diabetes mellitus Hypertension Hypertension Pyloric stenosis Pyloric stenosis Gout Gout

29. THANK YOU Clever father, clever daughters. Clever mother, clever sons.