Somatic segregation errors predominantly contribute to the gain or loss ofa paternal chromosome leading to uniparental disomy for chromosome 15

Paternal uniparental disomy (UPD) for chromosome 15 (UPD15), which is found in similar to 2% of Angelman syndrome (AS) patients, is much less frequent than maternal UPD15, which is found in 25% of Prader-Willi syndrome patien ts. Such a difference cannot be easily accounted for if 'gamete complementa tion' is the main mechanism leading to UPD. If we assume that non-disjuncti on of chromosome 15 in male meiosis is relatively rare, then the gain or lo ss of the paternal chromosome involved in paternal and maternal UPD15, resp ectively, may be more likely to result from a post-zygotic rather than a me iotic event. To test this hypothesis, the origin of the extra chromosome 15 was determined in 21 AS patients with paternal UPD15 with a paternal origi n of the trisomy. Only 4 of 21 paternal UPD15 cases could be clearly attrib uted to a meiotic error. Furthermore, significant non-random X-chromosome i nactivation (XCI) observed in maternal UPD15 patients (p < 0.001) provides indirect evidence that a post-zygotic error is also typically involved in l oss of the paternal chromosome. The mean maternal and paternal ages of 33.4 and 39.4 years, respectively, for paternal UPD15 cases are increased as co mpared with normal controls. This may be simply the consequence of an age a ssociation with maternal non-disjunction leading to nullisomy for chromosom e 15 in the oocyte, although the higher paternal age in paternal UPD15 as c ompared with maternal UPD15 cases is suggestive that paternal age may also play a role in the origin of paternal UPD15.