L3: Autosomal Recessive inheritance

• gene that causes phenotype lies on autosome

• phenotypes appears if imparied gene function on both alleles (bi-allelic)

• one normal allele = sufficient to maintain normal function (heterozygosity)

offspring

a) 25 % healthy, 50 % carrier, 25 % affected

b) 50 / non-carriers; 50 % carriers

c) 2/3 carrier, 1/3 healthy

= Pseudodaminance

• affected + heterozygot -> 50 % carrier + 50 % affected

• in pedigree: looks like autosomal dominant

• only homozygous or compound heterozygous carriers of a pathogenic variant manifest a phenotype

• both genders are equally affected

• metabolic disorders (esp. enzyme defects) = frequent

• transmission comes from both parents, who are heterozygous healthy carriers of a pathogenic variant

• often manifestation seems sporadic (few children!)

• consanguinity increases the likelihood for the manifestation of autosomal recessive diseases

• de novo mutations play an important role and are normally not detectable -> functional tests to detect if cis or trans

p^2 + 2pq + q^2 = 1

p + q = 1

2pq: frequency of heterozygotes

p^2 = AA (healthy)

q^2 = aa (affected / incidence of disease)

• non-random mating (alters frequency of p and q)

• small population size (alters frequency of p and q)

• gene flow (migration) (alters frequency of p and q)

• mutation (increases q)

• selection of heterozygotes (increases q)

• Ellis-van-Creveld syndrome = predominant in Amish people (UK)

  • founder mutation: 1 person emmigrated -> all EVC patient = offspring of him

  • EVC gene mutation: c.1886+5G>T

• franko-canadian disorders

• Ashkinasi mutations (Germany/Israel) -> bc. of only marriage within allowed community (jewish)

anemia + malaria —> associated mutations:

• sickle-cell trait (A -> T // Glutamin -> Valin)

  healthy life, but risk of becoming homozygot offspring if both parents = heterozygot

• main symptom: muscle hypotonia

• motorneuron disease

• caused by homozygous deletion of exon 7 and 8 of SMN1 gene (located on chr. 5)

• 4 forms (different severity/age of onset)

pseudogene = SMN1

• type I: 2x SMN1

• type II: 3x SMN1

• type III: 4x SMN1

—> copy number determines severity

• 1 substitution in exon 7 => splice out exon 7

  • regular intrafetal (spine) injection -> risk of infection

  • but keeps function or regain of function

• gene therapy = very expensive (only needs to be approved once) -> do as early as possible; no previous adeno-virus infection; bc. of adeno-virus vector