The Prader-Willi syndrome (PWS) and the Angelman syndrome (AS) are caused by the loss of function of imprinted genes in proximal 15q. In approximately 2%-4% of patients, this loss of function is due to an imprinting defect. In some cases, the imprinting defect is the result of a parental imprint-switch failure caused by a microdeletion of the imprinting center (IC). Here we describe the molecular analysis of 13 PWS patients and 17 AS patients who have an imprinting defect but no IC deletion. Heteroduplex and partial sequence analysis did not reveal any point mutations of the known IC elements, either. Interestingly, all of these patients represent sporadic cases, and some share the paternal (PWS) 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 inherited from the paternal grandmother. This suggests that the grandmaternal imprint was not erased in the father's germ line. In seven informative AS patients reported here and in three previously reported patients, 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 germ line or postzygotically. We conclude (1) that the incorrect imprint in non-IC-deletion cases is the result of a spontaneous prezygotic or postzygotic error, (2) that these cases have a low recurrence risk, and (3) that the paternal imprint may be the default imprint.

Imprinting of the Prader-Willi/Angelman syndrome region on human chromosome 15 is regulated by an imprinting centre (IC), which spans 5' exons of the gene encoding the small nuclear ribonucleoprotein N ( SNRPN ). The IC/ SNRPN transcripts are initiated at two alternative start sites, which share a high degree of sequence similarity with each other and with two newly identified sites 63 and >700 kb further upstream. Three of these sites are hypermethylated on the maternal chromosome, whereas one displays an oppositemethylation pattern. We have also identified novel splice variants of the IC/ SNRPN transcripts and hitherto undetected exons. One of these exons, which we designate u5, is deleted in all Angelman syndromepatients with a microdeletion of the IC. We conclude that elements of the IC region have undergone multiple duplication events and that u5 or a sequence close by may play a role in maternal imprinting.

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