Allele-specific replication differences have been observed in imprinted chromosomal regions. We have exploited this characteristic of an imprinted region by using FISH at D15S9 and SNRPN (small nuclear ribonucleo protein N) on interphase nuclei to distinguish between Angelman and Prader-Willi syndrome patient samples with uniparental disomy of chromosome 15q11-q13 (n = 11) from those with biparental inheritance (n = 13). The familial recurrence risks are low when the child has de novo uniparental disomy and may be as high as 50% when the child has biparental inheritance. The frequency of interphase cells with asynchronous replication was significantly lower in patients with uniparental disomy than in patients with biparental inheritance. Within the sample population of patients with biparental inheritance, those with altered methylation and presumably imprinting center mutations could not be distinguished from those with no currently detectable mutation. This test is cost effective because it is performed on interphase cells from the same hybridized cytological preparation in which a deletion is excluded, and additional specimens are not required to determine the parental origin of chromosome 15.