Genetic Disorders

1. Genetic Disorders

2. Genomics • Study of all genes in the genome and their interactions • Two most common DNA variations • Single-nucleotide polymorphisms • Copy number variations Epigenetics Heritable changes in gene expression that are not caused by alterations in DNA sequence

3. Classification • Disorders related to mutations in single genes with large effects (Mendelian disorders) • Chromosomal disorders • Complex multigenic disorders

4. Mutations • Permanent change in the DNA • Interfers with protein synthesis at various levels • Point mutation • Within coding sequences • Within noncoding sequences • Frameshift mutation • Deletions • Insertions • Trinucleotide-repeat mutations • Amplifications, dynamic

5. Mendelian Disorders • Autosomal dominant • Autosomal recessive • X-linked

6. Autosomal Dominant • Manifested in the heterozygous state • Some proportion due to a new mutation • Incomplete penetrance • Variable expressivity • Influence of environmental factors • Age of onset delayed in many conditions • Most are loss-of-function mutations • Table 5-1 common disorders

7. Autosomal Recessive • Largest category of mendelian disorders • Trait does not usually affect the parents • Siblings have a ¼ chance of having the trait • Think about consanguinity if mutant gene is rare • Expression of the defect tends to be more uniform • Complete penetrance is common • Onset is frequently early in life • New mutations are rarely detected clinically • Many of the mutated genes encode enzymes • Table 5-2 common disorders

8. X-linked Disorders • Most are recessive • Few X-linked dominant ( e.g. vitamin D- resistant rickets) • Affected male does not transmit the disorder to his sons, but all daughters are carriers • The heterozygous female usually does not express the full phenotypic change because of the paired normal allele • Table 5-3 common disorders

9. Biochemical and Molecular Basis of Mendelian Disorders • Enzyme defects and their consequences • Accumulation of substrate • Decreased amount of end product • Failure to inactivate a tissue-damaging substrate • Defects in membrane receptors and transport systems • Alterations in the structure, function, or quantity of nonenzyme proteins • Mutations resulting in unusual reactions to drugs

10. Disorders associated with Defects in Structural Proteins • Marfan syndrome • Disorder of connective tissues • Defect in fibrillin-1 • Skeletal abnormalities • Ocular changes • Cardiovascular lesions – life-threatening • Ehlers-Danlos syndromes • Defect in the synthesis or structure of fibrillar collagen

11. Disorders associated with Defects in Receptor Proteins • Familial hypercholesterolemia • Mutation in the gene encoding the receptor for LDL, which is involved in the transport and metabolism of cholesterol

12. Disorders associated with Defects in Enzymes • Lysosomal Storage diseases • Tay-Sachs • Niemann-Pick DiseaseType A,B,C • Gaucher disease • Mucopolysaccharidoses • Gycogen storage diseases • Hepatic forms • Myopathic forms • Miscellaneous forms • Alkaptonuria

13. Disorders associated with Defects in Proteins that Regulate Cell Growth • Proto-oncogenes • Tumor-suppressor genes • Important in the pathogenesis of tumors

14. Complex Multigenic Disorders • Polymorphism • Common disease/common variant hypothesis • Environmental factors • Difficult to distinguish from mendelian disease at times

15. Chromosomal Disorders • Normal karotype • G banding • Terminology • Structural abnormalities • Aneuploidy • Nondisjunction • Anaphase lag • Mosaicism • Deletion • Ring chromosome • Inversion • Isochromosome • Translocation • Balanced reciprocal • Robertsonian

16. Cytogenic Disorders involving Autosomes • Trisomy 21 (Down syndrome) • Trisomy 18 (Edwards syndrome) • Trisomy 13 (Patau syndrome • Chromosome 22q11.2 Deletion syndrome

17. Trisomy 21 • 1/700 incidence in US • Maternal age • Flat facial profile, oblique palpebral fissures, epicanthic folds, intellectual disability,hypotonia • 40% congenital heart disease • Increased risk of leukemia • Abnormal immune responses • Alzheimer disease after 40 years of age • Figure 5-21 clinical features of trisomies

18. Chromosome 22q11.2 Deletion Syndrome • DiGeorge syndrome • Thymic dysplasia  immunodeficiency • Parathyroid hypoplasia  hypocalcemia • Cardiac malformations • Facial anomalies • Velocardiofacial syndrome • Facial dysmorphism • Cleft palate • CVS anomalies • Learning disabilities

19. Cytogenic Disorders involving Sex Chromosomes • Lyon hypothesis • Klinefelter syndrome • Turner syndrome • Hermaphroditism • Pseudohermaphroditism

20. Lyon Hypothesis • Only one of the X chromosomes is genetically active • The other is rendered inactive at random at about day 16 of embryonic life • Inactivation of the same X persists in all cells derived from each precursor cell • Barr body • Not all of the genes on the inative X are switched off • Both Xs are required for normal oogenesis

21. Klinefelter Syndrome • Male hypogonadism • Two or more X and one or more Y • Elongated body, gynecomastia • Reduced spermatogenesis and male infertility • Increased risk of breast cancer, extragonadal germ cell tumors, autoimmune disorders • Longest CAG repeat X chromosome remains active

22. Turner Syndrome • Complete or partial monosomy of the X chromosome • Hypogonadism in phenotypic females • Single most important cause of primary amenorrhea • Figure 5-23 Clinical features

23. Hermaphroditism and Pseudohermaphroditism • Genetic sex • Gonadal sex • Ductal sex • Phenotypic or genital sex • True hermaphrodite – presence of both ovarian and testicular tissue • Pseudohermaphrodite – disagreement between phenotypic and gonadal sex • Female – excess androgen • Male – complete androgen insensitivity syndrome

24. Single-Gene Disorders with Nonclassic Inheritance • Diseases caused by trinucleotide-repeat mutations • Disorders caused by mutation in mitochondrial genes • Diseases associated with genomic imprinting • Diseases associated with gonadal mosaicism

25. Fragile X Syndrome • Prototype of mutation with long repeating sequence of three nucleotides • Second most common genetic cause of intellectual disability after Down syndrome • Macro-orchidism • Normal carrier males • Affected females –much higher than in other x-linked recessive disorders • Risk of phenotypic effects depends upon position in pedigree • Anticipation – worsens with each successive generation

26. Leber Hereditary Optic Neuropathy • Prototype of mitochondrial inheritance disorder • Maternal inheritance • mtDNA complement of the zygote is derived entirely from the ovum • Genes incode for enzymes involved in oxidative phosphorylation • Threshold effect • Neurodegenerative disease – progressive loss of central vision

27. Genomic Imprinting • Imprinting selectively inactivates either the maternal or the paternal allele • Uniparentaldisomy • Angelman • Deletion of maternally-derived chromosome 15 • “Happy puppet” – intellectual disability, ataxia, inappropriate laughter, seizures • Prader-Willi • Deletion of paternally-derived chromosome 15 • Intellectual disability, hypogonadism, hypotonia, hyperphagia, short stature, obesity, small hands and feet

28. Molecular Diagnosis of Genetic Diseases • Indications for analysis of germ line genetic alterations • Indications for analysis of acquired genetic alterations • PCR and detection of DNA sequence alterations • Polymorphic markers and molecular diagnosis • Molecular analysis of genomic alterations • Southern blot • FISH • Array CGH • Epigenetic alterations – do not alter the DNA sequence • RNA analysis- RNA viruses – HIV, HCV

29. Indications for Germline Alterations • Prenatal genetic analysis • Amniocentesis, chorionic villus sample, or umbilical cord blood • Mother of advanced age • Parent who is a carrier of a translocation or inversion • Parent with a previous child with a chromosomal abnormality • Fetus with ultrasound-detected abnormalities • Parent who is a carrier of an X-linked disorder • Abnormal levels of triple markers (AFP. BetaHCG, estriol)

30. Indications for Germline Alterations • Postnatal genetic analysis • Peripheral blood lymphocytes • Multiple genetic anomalies • Unexplained intellectual disability and/or developmental delay • Suspected aneuploidy • Suspected unbalanced autosome • Suspected sex chromosome abnormality • Suspected fragile-X • Infertility • Multiple spontaneous abortions

31. Indications for Acquired Alterations • Diagnosis and management of cancer • Detection of tumor-specific alterations • Determination of clonality • Identification of specific alterations that can direct treatment • Determination of treatment efficacy • Determination of Gleevec-resistant forms of tumors

32. Indications for Acquired Alterations • Diagnosis and management of infectious diseases • Detection of microorganism-specific genetic material for diagnosis • Identification of alterations that are associated with drug resistance • Determination of treatment efficacy