Origin of uniparental disomy 15 in patients with Prader-Willi or Angelman syndrome

Maternal uniparental disomy (UPD) accounts for similar to 25% of Prader-Wil li patients (PWS) and paternal UPD for about 2-5% of Angelman syndrome (AS) patients. These findings and the parental origin of deletions are evidence of genomic imprinting in the cause of PWS and AS. The natural occurrence o f UPD individuals allows the study of meiotic mechanisms resulting in chrom osomal nondisjunction (ND), We selected patients with UPD15 from our sample of 30 PWS and 40 AS patients to study the origin of ND and the recombinati on along chromosome 15, These patients were analyzed with 10 microsatellite s throughout the entire chromosome 15 (D15S541, D15S542, D15S11, D15S113, G ABRB3, CYP19, D15S117, D15S131, D15S984, D15S115). The analysis disclosed s even heterodisomic PWS cases originating by meiosis I (MI) ND (four showed recombination and three no recombination), and one isodisomic PWS UPD15 ori ginating by postzygotic duplication. Among the five paternal UPD15, we dete cted four isodisomies, three of which showed homozigosity for all markers, corresponding to a mitotic error, and one case originating from a paternal MII ND. Our results indicate that besides maternal MI and MII ND, paternal ND occurs when a PWS UPD15 patient originates from mitotic duplication of t he maternal chromosome 15, ND events in AS are mainly due to mitotic errors , but paternal MII ND can occur and give origin to an AS UPD15 individual b y two different mechanisms: rescue of a trisomic fetus or fertilization of a nullisomic egg with the disomic sperm, and in this case paternal and mate rnal ND are necessary. (C) 2000 Wiley-Liss, Inc.