Prenatal diagnosis of uniparental disomy 15 following trisomy 15 mosaicism.

Maternal uniparental disomy 15 (UPD15), responsible for approximately 25 per cent of Prader-Willi syndrome cases, is usually caused by maternal meiosis I non-disjunction associated with advanced maternal age. These cases may initially be detected as mosaic trisomy 15 during routine prenatal diagnostic studies. In such cases, PCR (polymerase chain reaction) microsatellite analysis of uncultured cells makes prospective prenatal diagnosis for UPD15 possible with results available in 2-4 days. We have performed molecular analyses on a series of seven cases of mosaic trisomy 15 identified in amniotic fluid (AF, n = 3) or chorionic villus samples (CVS, n = 4) from patients initially referred for advanced maternal age or abnormal triple screen. In all cases, the maternal ages were > or = 35 years and maternal meiosis I non-disjunction was documented as the cause of the trisomy in all informative cases (n = 5). Of the three case with mosaic trisomy 15 at amniocentesis, two showed the presence of the trisomy in the fetus. Molecular analysis showed one case with maternal UPD15 in the euploid cell line and one case with biparental inheritance. Both of these families elected to terminate the pregnancies based on the presence of true fetal mosaicism. In the third case, low-level trisomy 15 mosaicism in the amniotic fluid was not confirmed in a follow-up amniotic fluid sample and molecular analysis indicated biparental inheritance in the fetus. For the four trisomy 15 mosaics detected at CVS, molecular analysis was performed on direct amniotic fluid cell lysates for prospective diagnosis of UPD at 14-16 weeks' gestation. Follow-up cytogenetic analysis of the amniotic fluid in all four cases was normal, indicating confined placental mosaicism. Molecular analysis showed one of these four cases to have maternal heterodisomy 15. Based on the likelihood of Prader-Willi syndrome due to maternal UPD15, the couple chose to terminate the pregnancy. The total of two of seven cases of trisomy 15 mosaicism resulting in UPD15 is consistent with the theoretical expectation of one-third and indicates a high risk of UPD in such pregnancies. Therefore, UPD testing should be offered in all cases of mosaic trisomy 15 encountered in CVS or amniocentesis.