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PATTERNS OF INHERITANCE

PATTERNS OF INHERITANCE. dr. R. Sutomo , Sp.A , Ph.D. Pattern of inheritance Why concerns?. Genetic counseling Impact of genetic counseling Not for reducing the incidence Option for therapy frequently unavailable. Why genetic counseling?. Recurrence risk assessment

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PATTERNS OF INHERITANCE

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  1. PATTERNS OF INHERITANCE dr. R. Sutomo, Sp.A, Ph.D

  2. Pattern of inheritanceWhy concerns? • Genetic counseling • Impact of genetic counseling • Not for reducing the incidence • Option for therapy frequently unavailable

  3. Why genetic counseling? • Recurrence risk assessment • Well-informed-based decision • Psychological impacts • Adjustment • Predicting prognosis

  4. Studying pattern of inheritanceHow to investigate? • Family studies • Drawing a pedigree

  5. Family studies • A particular trait or disorder  genetic and hereditary? • observation of the way in which it is transmitted from one generation to another, or • on study of its frequency among relatives • Taking a family history can, in itself, provide a diagnosis

  6. Family tree • A family tree is a shorthand system of recording the pertinent information about a family • Begins with the person through whom the family came to the attention of the investigator index case, proband or propositus, or proposita (for female)

  7. Mendelian character • Its presence and absence depends on the genotype at a single locus • A certain genotype at one locus is necessary and sufficient for the character to be expressed • Does not mean that the character is programmed by only one pair of genes • ±10.000 mendelian characters

  8. Mendelian inheritance • Remind: dominance and recessiveness are properties of characters, notgenes • Character: • Dominant  manifest in heterozygote • Recessive  notmanifest in heterozygote

  9. Symbols in pedigree Individuals

  10. Symbols in pedigree Individuals

  11. Symbols in pedigree Relationships

  12. Symbols in pedigree Assisted reproductive scenarios

  13. Mendelian inheritance • Autosomal dominant • Autosomal recessive • X-linked dominant • X-linked recessive • Y-linked

  14. Basic Mendelianinheritance Autosomal dominant Autosomal recessive X-linked recessive X-linked dominant Y-linked

  15. Autosomal dominant inheritance

  16. Pedigree of autosomal dominant inheritance

  17. Features of AD inheritance • An affected person usually has at least one affected parent • No skipping of generation • Affects either sex • Transmitted by either sex • Affected x unaffected mating  child: 50% chance of being affected (assuming that the affected parent is heterozygous)

  18. RISK CALCULATION Dd x Dd Dd x dd ?????? Affected : unaffected 1 : 1

  19. Autosomal dominant disorders • Achondroplasia • Myotonic dystrophy • Neurofibromatosis • Osteogenesisimperfecta • Tuberous sclerosis • Facioscapulohumeral dystrophy • Acute intermittent porphyria • Acute intermittent porphyria • Familial breast cancer (BRCA 1, BRCA 2 • Familial hypercholesterolemia • Familial adenomatouspolyposis • Charcot-Marie-Tooth disease • Huntington disease

  20. Unusual autosomal dominant inheritance • Non-penetrance • Variable expression • Anticipation • De novo mutation • Genetic imprinting

  21. Non-penetrance • Penetrance: the probability that a person with a certain genotype will manifest the character • Non-penetrance failure of a dominant character to manifest • Theoretically, dominant character 100% penetrance • In fact  continuum characters: • Fully penetrant mendelian   multifactorials • Complicating the genetic counseling

  22. Variable expression • Different family members different features of the disease/syndrome • Waardenberg syndrome • Hearing loss • Different color eyes • White forelock • Premature graying of hair

  23. Genetic anticipation • The phenotype is more severe in successive generation • Unclear mechanism • Examples: • Myotonic dystrophy • Huntington disease

  24. Genetic imprinting • Normally, genes are equally express either from paternal or maternal copies • Genetic imprinting: expression depends on the origin of the gene/genes paternal or maternal • Paternal imprinting Prader-Willi syndrome • Maternal imprinting  Angelman syndrome

  25. The disorder manifests only when the gene is inherited from the mother Genetic imprinting

  26. Genetic imprinting • The disorder manifests only when the gene is inherited from the father

  27. Prader Willy SyndromeAngelman Syndrome • Prevalence: 1/10.000-15.000 • Chromosome 15q11-q13 • Genotipe • Paternal/maternal deletion of 5q11-q13 (70%) • Uniparental disomy (UPD) (25-30%) • Maternal UPD (PWS) • Paternal UPD (AS) • Defect of imprinting center in 15q11-q13 (-) paternal   PWS maternal  (-)  AS

  28. PRADER-WILLI SYNDROME Obesity Short stature Peeled skin Almond-shaped eyes Hypotonicity Small hands and feet Narrowed nasal bridge Down-turned mouth Narrowed bitemporal Hypogonadism Mental reterd Dysartria Sticky saliva

  29. ANGELMAN SYNDROME (Happy puppet syndrome) Flat occiput Prominent mandible Microcephaly(~2 yo) Hypopigmentation Strabismus Contracture Happy face Hyperactivity Ataxic gait Hand flapping Puppet-like movement Wide mouth Spaced teeth Chewing/ mouthing >> Severe MR Epilepsy Severe speech imp

  30. Newly occured mutation De novo mutation Autosomal recessive? X-linked recessive?

  31. Complicated AD pattern What’s the shortcut...? Be familiar with common AD disorders

  32. Autosomal recessive inheritance

  33. Pedigree of AR inheritance

  34. Features of AR inheritance • Affected people are usually born to unaffected parents  WHY? • Parent of affected people are usually asymptomatic carrier • Increased incidence of parental consanguinity  WHY? • Affect either sex • After the birth of an affected child, each subsequent child has a 25% chance of being affected

  35. Segregation of AR alleles

  36. AR inheritance affected carrier

  37. Effect of consanguinity on AR inheritance

  38. Autosomal recessive disorders

  39. Complication to AR inheritancePseudo-dominant • Common recessive conditions can give a pseudo dominant pedigree pattern • Blood group O may be seen in successive generation because of repeated marriages of group O people with heterozygotes

  40. Complication to AR inheritancePseudo-dominant • A individual who is homozygous for an autosomal recessive disorder marries a carrier of the same disorder, their children have a 1 in 2 (50%) chance of being affected

  41. Complication to AR inheritanceComplementation • Two affected parents may give unaffected child • The disorder is associated with defect in several genes • The children will be normal whenever the parents carry mutation in different genes • AR congenital profound hearing loss • Usher syndrome: hearing loss + retinitis pigmentosa • Associated with defects in 8 different genes

  42. Complementation • Locus heterogeneity • Mutational heterogeneity

  43. Genocopy • Disorders with the same phenotype due to different genetic loci • Phenocopy • Disorders with the same phenotype being the result of environmental causes

  44. For life we learn, not for school

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