SPORADIC IMPRINTING DEFECTS IN PRADER-WILLI-SYNDROME AND ANGELMAN-SYNDROME - IMPLICATIONS FOR IMPRINT-SWITCH MODELS, GENETIC-COUNSELING, AND PRENATAL-DIAGNOSIS

The Prader-Willi syndrome (PWS) and the Angelman syndrome (AS) are cau sed by the loss of function of imprinted genes in proximal 15q. In sim ilar to 2%-4% of patients, this loss of function is due to an imprinti ng defect. In some cases, the imprinting defect is the result of a par ental imprint-switch failure caused by a microdeletion of the imprinti ng center (IC). Here we describe the molecular analysis of 13 PWS pati ents and 17 AS patients who have an imprinting defect but no IC deleti on. Heteroduplex and partial sequence analysis did not reveal any poin t mutations of the known IC elements, either. Interestingly, all of th ese patients represent sporadic cases, and some share the paternal (PW S) or the maternal (AS) 15q11-q13 haplotype with an unaffected sib. In each of five PWS patients informative for the grandparental origin of the incorrectly imprinted chromosome region and four cases described elsewhere, the maternally imprinted paternal chromosome region was inh erited from the paternal grandmother. This suggests that the grandmate rnal imprint was not erased in the father's germ line. In seven inform ative AS patients reported here and in three previously reported patie nts, the paternally imprinted maternal chromosome region was inherited from either the maternal grandfather or the maternal grandmother. The latter finding is not compatible with an imprint-switch failure, but it suggests that a paternal imprint developed either in the maternal g erm line or postzygotically. We conclude (1) that the incorrect imprin t in non-IC-deletion cases is the result of a spontaneous prezygotic o r postzygotic error, (2) that these cases have a low recurrence risk, and (3) that the paternal imprint may be the default imprint.