Deletions and duplications of the 15q11-q13 region in spermatozoa from Prader-Willi syndrome fathers

Prader-Willi syndrome (PWS) is a genomic disorder mostly caused by deletions of 15q11-q13 region (70%). It has been suggested that the particular genomic architecture of 15q11-q13 region, characterized to be flanked by low copy repeats, could predispose it to Non-Allelic Homologous Recombination (NAHR). However, no studies in gametes of fathers of PWS individuals have been published to date. The objective of the study was to assess the incidence of 15q11-q13 deletions and duplications in spermatozoa from PWS fathers and to appraise the value of the data obtained for the estimation of the risk of recurrence for the syndrome. Semen samples from 16 fathers of PWS individuals and 10 control donors, were processed by triple-color fluorescence in situ hybridization. A customized combination of probes was used to discriminate between normal, deleted and duplicated sperm genotypes. A minimum of 10 000 sperm were scored for every single sample. A significant increase in the frequency of 15q11-q13 deletions and duplications were observed in PWS fathers (0.90 +/- 0.14%) compared with control donors (0.47 +/- 0.07%). Ten out of 16 individuals contributed to this population increase (P < 0.01), suggesting a predisposition for 15q11-q13 reorganizations. Statistical differences were observed in the frequency of 15q11-q13 deletions and duplications in fathers of PWS individuals (0.59 versus 0.31%; P = 0.001), indicating that intra-chromatid NAHR exchanges also substantially contribute to the rearrangements. Results demonstrated the increased susceptibility of some fathers of PWS individuals to generate 15q11-q13 deletions, suggesting that the screening of anomalies in sperm should be advisable as a valuable complement for genetic counseling.