L4.1: Gonosomal inheritance

• mother affected -> 50 % sons, 50 % daughters affected

• father affected -> 100 % daughter = affected; son = 100 % unaffeceted (no male to male inheritance)

• gender imbalance

• mutations in the IKBKG gene (Xq28)

  • IKBKG involved in inflammation, immunity, cell survival

• only affected women // miscarriage of sons

  • daughters survive, bc random inactivation of maternal or paternal X-chr. in early embryogenesis (lyonization) -> can also be transferred to children

  • males = hemizygous (bc. only one X chr.)

= very rare

• hemizygous = lethal diseases:

  • incontinentia pigmenti (IP)

  • Rett-Syndrome

  • Vitamin-D-resistant rickets with hypophosatemia

  • Alport-Syndrome

• men with mild or no symptoms

  • Epileptic encephalopathy type 9

  • Craniofrontonasal syndrome (mutation in EFNB1 gene)

• no male to male transmission

• all daughters of affected male = affected

• men w/o symptoms = never carrier

• sons of female carriers have 50 % probability to be affected

• half of the daugthers of carriers are carriers themselves

• lyonization // functional hemizygosity can cause exceptions from rule according to females

• type A: deficiency in coagulation factor VIII

• type B: deficiency in coagulation factor IX

• BUT: identical clinical phenotype (= bleeding into joint/muscles)

• parent specific mutations in hemophilia A:

  • F8 gene Xq28 (PAR = pseudo-autososmal regioins)

  • inversion within chromosome, point mutation (paternal)

  • maternal deletion (cross-over, meiosis)

  • risk = old parents

• disease of English Monarchie (Queen Victoria)

• expansion of CGG triplet in FMR1 gene

  • = related to the brain

  • different repeat numbers (intermediate will grow in size); full mutation: + methylation

Garber et al, Eur J Hum Genet 2008

distinct in male and females