THE IMPACT OF IMPRINTING - PRADER-WILLI-SYNDROME RESULTING FROM CHROMOSOME-TRANSLOCATION, RECOMBINATION, AND NONDISJUNCTION

Prader-Willi syndrome (PWS) is most often the result of a deletion of bands q11.2-q13 of the paternally derived chromosome 15, but it also o ccurs either because of maternal uniparental disomy (UPD) of this regi on or, rarely, from a methylation imprinting defect. A significant num ber of cases are due to structural rearrangements of the pericentromer ic region of chromosome 15. We report two cases of PWS with UPD in whi ch there was a meiosis I nondisjunction error involving an altered chr omosome 15 produced by both a translocation event between the heteromo rphic satellite regions of chromosomes 14 and 15 and recombination. In both cases, high-resolution banding of the long arm was normal, and F ISH of probes D15S11, SNRPN, D15S10, and GABRB3 indicated no loss of t his material. Chromosome heteromorphism analysis showed that each pati ent had maternal heterodisomy of the chromosome 15 short arm, whereas PCR of microsatellites demonstrated allele-specific maternal isodisomy and heterodisomy of the long arm. SNRPN gene methylation analysis rev ealed only a maternal imprint in both patients. We suggest that the ch romosome structural rearrangements, combined with recombination in the se patients, disrupted normal segregation of an imprinted region, resu lting in uniparental disomy and PWS.