Recently we published a review about genetic counseling and the provision of risk information in Angelman syndrome (AS) ]. However, since then, new evidence indicates that gonadal mosaicism may affect recurrence risk in the subset of AS patients who are affected as the result of UBE3A gene mutations. wrote a summary of their experience in mutation analysis of the UBE3A gene in 35 sporadic and 10 familial cases of AS. Mutations were identified in 13 individuals (8 familial and 5 sporadic), and in 3 instances, mosaicism (somatic or gonadal) was identified. Thus, mosaicism is present in 20% of sporadic cases and in 25% of familial AS cases in the population studied. Although these numbers may not prove to be representative of the true risks of mosaicism when larger numbers of individuals are studied, the risks appear to be significant enough to caution families about the potential for gonadal mosaicism when providing genetic counseling based on UBE3A results. If a UBE3A mutation is found in the affected individual and not in the mother, then the risk of recurrence may not be less than 1%. In these instances, the possibility of prenatal diagnosis in subsequent pregnancies should be discussed with the family. An additional cautionary note is that because of the possibility of gonadal mosaicism, haplotype analysis may provide misleading information regarding the affected status of a fetus when the haplotype is the same as that of the index case in the family. However, a discordant fetal haplotype could be used to infer that the fetus is unaffected.
Gonadal mosaicism was also identified in several instances in which AS resulted from imprinting center (IC) mutations. In fact, gonadal mosaicism for IC mutations might be quite common, given that Saitoh et al.
[1996] identified two germ line mosaics in six families with identifiable IC mutations. described a family with two AS children with biparental inheritance of the 15q11-q13 region and an abnormal methylation pattern at D15S63, in which prenatal diagnosis identified a fetus with the same maternal hap-lotype as the affected sibs, but who had normal methylation studies by fetal cord blood analysis. The mother in this instance had normal methylation studies and was considered to be a gonadal mosaic. It appears that normal results of maternal methylation studies do not necessarily mean that future pregnancies are not at increased risk. Likewise, abnormal maternal methylation study results do not necessarily mean that future pregnancies will be at 50% risk.