Cytogenetic and age-dependent risk factors associated with uniparental disomy 15

Prader-Willi syndrome (PWS) results primarily from either a paternal deletion of 15q11-q13 or maternal uniparental disomy (UPD) of chromosome 15. Including the present and published cases, more than 120 patients with maternal UPD of human chromosome 15 have been ascertained. Investigation of chromosome 15 markers indicates that approximately 71 per cent of the additional maternal chromosomes were the result of meiosis I segregation errors, 13 per cent were the result of meiosis II errors, and 16 per cent resulted from post-zygotic duplication of one chromosome 15. An increase in maternal age is associated with UPD cases due to meiotic errors. The age-specific risk for UPD(15) is analysed and shows an exponential increase with maternal age which is similar to that observed for trisomy 21. For women greater than or equal to 40 years of age, the risk for UPD(15) is approximately 1/3400 livebirths. The frequency of chromosome aberrations associated with UPD(15) is also discussed. Two types of aberrations are at significantly increased risk of fetal UPD(15): de novo (or inherited) isochromosome 15 and confined placental mosaicism for trisomy 15. Two additional abnormalities, de novo small marker chromosomes derived from 15, e.g., idic15(pter-q11:q11-pter), and familial Robertsonian translocations involving chromosome 15, appear to have a mildly increased risk of UPD(15).