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

Abstract

Paternal uniparental disomy (UPD) for chromosome 15 (UPD15), which is found in approximately 2% of Angelman syndrome (AS) patients, is much less frequent than maternal UPD15, which is found in 25% of Prader-Willi syndrome patients. Such a difference cannot be easily accounted for if 'gamete complementation' is the main mechanism leading to UPD. If we assume that non-disjunction of chromosome 15 in male meiosis is relatively rare, then the gain or loss of the paternal chromosome involved in paternal and maternal UPD15, respectively, may be more likely to result from a post-zygotic rather than a meiotic event. To test this hypothesis, the origin of the extra chromosome 15 was determined in 21 AS patients with paternal UPD15 with a paternal origin of the trisomy. Only 4 of 21 paternal UPD15 cases could be clearly attributed to a meiotic error. Furthermore, significant non-random X-chromosome inactivation (XCI) observed in maternal UPD15 patients (p < 0.001) provides indirect evidence that a post-zygotic error is also typically involved in loss 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 compared with normal controls. This may be simply the consequence of an age association with maternal non-disjunction leading to nullisomy for chromosome 15 in the oocyte, although the higher paternal age in paternal UPD15 as compared with maternal UPD15 cases is suggestive that paternal age may also play a role in the origin of paternal UPD15.

Angelman syndrome (AS, MIM 105830)

“…29 Mechanisms of UPD formation are trisomy rescue, gamete complementation, mitotic duplication and post-fertilization errors. 30 The mechanism of paternal UPD of chromosome 15 was described by Robinson et al, 31 showing a somatic segregation error in about 75% of these paternal UPD15 cases. A milder clinical phenotype in patients with paternal UPD has been suggested compared with AS patients with a deletion.…”

Clinical and genetic aspects of Angelman syndrome

“…44,103 In contrast to PWS, the paternal UPD observed in AS is most likely to be postzygotic in origin. 104 …”

Low incidence of UPD in spontaneous abortions beyond the 5th gestational week

“…31 Non random X-inactivation was also detected in 25% of maternal UPD 15 cases. 32 Furthermore, recent data on human preimplantation embryos show a high rate of mosaic aneuploidy not only in the two to eight cell stage embryo 11 but also in the inner cell mass (ICM) cell lineages in enhanced-hatching blastocyst. 33 It, therefore, appears that rescue mechanisms of postzygotic non-disjunctions occur at a later developmental stage in the majority of cases.…”