GENETIC DISORDER, MUTATIONS, CYTOGENETIC DISORDERS

1. GENETIC DISORDER, MUTATIONS, CYTOGENETIC DISORDERS Dr Tamil Nila

2. Concepts • Genetics is the study of genes • 23 pairs of chromosomes • 22 pairs – Autosomal • One pair – sex chromosome • 20000 – 30000 genes • Every gene has 2 alleles – one paternal + one maternal • Exon – Coding region of DNA (1.5%) • Intron – Non coding region of DNA (98.5%)

3. Definitions • Heterozygous • Homozygous • Dominant inheritance • Recessive • Co-dominant • Pleiotropy • Incomplete penetrance • Variable expressivity • Anticipation

4. Mutation Point mutation Silent Missense Non sense Frame shift mutation

5. Chromosomal abnormalities • Structural • Deletion • Insertion • Translocation • Ring chromosome • Iso chromosome • Inversion • Numerical • Aneuploidy • Monosomy • Trisomy

6. Epigenetics • Hereditary chemical modification in DNA/ Chromatin/ Histone at a functional level • No change in nucleotide sequence • Decreased gene expression • Processes • DNA methylation • Histone deacetylation

7. Diagnosis of genetic disorders • Cytogenetics • Karyotyping • FISH • Molecular genetics • MLPA (Multiple ligation probe amplification) • PCR • Microarray • Sequencing

8. Human Genetic disorders Mutations in single gene with large effects Chromosomal disorders Complex multigenic disorders

9. Mendelian disorders Autosomal Dominant Recessive X linked Dominant Recessive

10. Autosomal dominant • Male = Female • Expressed in heterozygous states • One parent is affected • Manifests in adulthood • No skip generations • Defect in structural proteins

11. Autosomal disorders • Huntington’s chorea • Hereditary spherocytosis • Adult onset Polycystic kidney disease • Von Hipple Lindau disease Von Willebrand disease • Dystrophia myotonica • Osteogenesis imperfecta • Marfan’s syndrome • Intermittent porphyria • Neurofibromatosis 1 • Achondroplasia • NF -2 • Tuberous sclerosis • Familial adenomatous polyposis Familial hypercholestrolemia He Has A Very DOMINANT Father

12. Autosomal recessive disorders • Male = Female • Homozygous state • When heterozygous – Carriers • Manifests in childhood/ infancy • Due to enzyme deficiency

13. Autosomal recessive disorders • Alpha -1- antitrypsin Ataxia telangiectasia Alkaptonuria • Beta-thalassemia • Cystic fibrosis Congenital Adrenal hyperplasia • Deafness • Emphysema • Friedrich’s Ataxia • Gaucher’s ataxia Glycogen storage disorder Galactosemia • Hemochromatosis Homocystinuria • Inborn errors of metabolism ABCDE…

14. X linked recessive disorders • Male >> Female • Females – Carriers • Females are affected when random X inactivation occurs • When Mother is a carrier • 50% sons are affected • 50% daughters are carriers • When Father is affected • All sons are normal • Al daughters are carriers Criss – Cross inheritance

15. X – Linked recessive diseases • Lesch Nyhan syndrome • Hemophilia A & B Hunter’s disease • Color blindness • G6PD deficiency • Duchenne muscular dystrophy • Chronic granulomatous disease • Agammaglobulinemia • Fabry’s disease Fragile X syndrome • Wiscott Aldrich syndrome Lady Harding College Girls Don’t Care About Foolish Words

16. X linked Dominant disorders • Mother is affected • Both sons and daughters are affected • Father is affected • Only daughters are affected

17. X – Linked Dominant • Rett’s syndrome • Alport syndrome • Vitamin D resistant rickets • Incontinentia pigmenti RAVI

18. Marfan’s Syndrome Defect in fibrillin 1 (FBN 1) and fibrillin 2 (FBN 2) gene Excess of TGf - β Elastin destroyed Hyperelasticity of skin Congenital contractural arachnodactyly

19. Clinical presentations Skeletal defects Tall stature Hyper extensible joints Dolicocephalic head Ocular defects Ectopia lentis Superotemporal dislocation of lens CVS defects MV prolapse Aortic dissection

20. Diagnosis & treatment • Revised Ghent’s criteria • Family history • Signs & symptoms • Fibrillin 1 gene mutation • Treatment • TGF – β blocker - Losartan

21. Ehlers – Danlos syndrome • Defects in collagen synthesis or assembly • Clinical features • Fragile & hyperextensible skin • Hypermobile joints • Ruptures on colon, cornea or large arteries • Poor wound healing

23. Familial hypercholestrelemia • Autosomal dominant • Mutations in the gene encoding for • LDL receptor • ApoB protein • Activating mutations of PCSK 9 • Clinical features • Elevated serum cholesterol • Atherosclerosis • Coronary artery disease • Xanthoma

24. Lysosomal storage diseases Disorders Enzyme deficiency Sphingolipidoses Gaucher’s disease Glucocerebrosidase Tay sach’s disease Hexosaminidase A Fabry disease Alpha galactosidase Krabbe disease Galactocerebrosidase Niemann pick disease Sphingomyelinase Mucopolysaccharidoses Hurler syndrome Alpha L iduronidase Hunter Syndrome Iduronate 2 sulphatase

25. Glycogen storage diseases Type Deficient enzyme I – Von Gierke Glucose – 6 – Phosphate II – Pompe Lysosomal α 1,4 glycosidase III – Cori Debranching enzyme IV – Anderson Branching Enzyme V - McArdle Muscle glycogen phosphorylase VI – Hers Hepatic Glycogen phosphorylase

26. Down syndrome – Trisomy 21 • Most common chromosomal disorder • Most common genetic cause of mental retardation • Pathogenesis • Meiotic non disjunction • Robertsonian translocation • mosaics • Complications • CVS – Endocardial cushion defect, VSD • GIT – duodenal atresia, Hirschsprung disease • Acute leukemia • Hypothyroidism • Premature Alzheimer’s disease

27. Klinefelter syndrome • Most common cause of male hypogonadism • More the X chromosome, more the mental retardation • Pathogenesis • Meiotic non dysjunction • Testicular biopsy • Leydig cell hyperplasia • Increased FSH, LH • Decreased testosterone

28. Turner syndrome • Most common cause of female hypogonadism • Pathogenesis • Meiotic non – dysjunction • Anaphase lag • Ring chromosome • Isochromosome • mosaics

29. Fragile X syndrome • X linked recessive disorder • Loss of function mutation in FMR 1 gene leading to increased CGG repeats • Most common inherited cause of mental retardation • Macro-orchidism

30. Prader – Willi syndrome • Maternal allele is silenced • Paternal allele – normal • Clinical features • Small bird like head • Mentally retarded • Respiratory problems • Obesity • Short lifespan • Hyperphagia • Hypogonadism • hypotonia

31. Angelman syndrome • Paternal gene is silenced • Maternal gene – normal • Clinical features • Inappropriate laughter • Stiff/ ataxic movements • Microcephaly • Seizures • Mental retardation

GENETIC DISORDER, MUTATIONS, CYTOGENETIC DISORDERS

GENETIC DISORDER, MUTATIONS, CYTOGENETIC DISORDERS

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GENETIC DISORDER, MUTATIONS, CYTOGENETIC DISORDERS