Sporadic imprinting defects in Prader-Willi syndrome and Angelman syndrome: Implications for imprint-switch models, genetic counseling, and prenatal diagnosis

Item Type:	Article
Title:	Sporadic imprinting defects in Prader-Willi syndrome and Angelman syndrome: Implications for imprint-switch models, genetic counseling, and prenatal diagnosis
Creators Name:	Buiting, K. and Dittrich, B. and Gross, S. and Lich, C. and Faerber, C. and Buchholz, T. and Smith, E. and Reis, A. and Buerger, J. and Noethen, M.M. and Barth-Witte, U. and Janssen, B. and Abeliovich, D. and Lerer, I. and van den Ouweland, A.M.W. and Halley, D.J.J. and Schrander-Stumpel, C. and Smeets, H. and Meinecke, P. and Malcolm, S. and Gardner, A. and Lalande, M. and Nicholls, R.D. and Friend, K. and Schulze, A. and Matthijs, G. and Kokkonen, H. and Hilbert, P. and Van Maldergem, L. and Glover, G. and Carbonell, P. and Willems, P. and Gillessen-Kaesbach, G. and Horsthemke, B.
Abstract:	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.
Keywords:	Angelman Syndrome, Prader-Willi Syndrome, Imprinting, Methylation
Source:	American Journal of Human Genetics
ISSN:	0002-9297
Publisher:	University of Chicago Press
Volume:	63
Number:	1
Page Range:	170-180
Date:	July 1998
Official Publication:	https://doi.org/10.1086/301935
PubMed:	View item in PubMed

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