TY - JOUR
T1 - Sporadic imprinting defects in Prader-Willi syndrome and Angelman syndrome: Implications for imprint-switch models, genetic counseling, and prenatal diagnosis
AU - Buiting, Karin
AU - Dittrich, Bärbel
AU - Groß, Stephanie
AU - Lich, Christina
AU - Färber, Claudia
AU - Buchholz, Tina
AU - Smith, Ellie
AU - Reis, André
AU - Bürger, Joachim
AU - Nöthen, Markus M.
AU - Barth-Witte, Ulli
AU - Janssen, Bart
AU - Abeliovich, Dvorah
AU - Lerer, Israela
AU - Van Den Ouweland, Ans M.W.
AU - Halley, Dicky J.J.
AU - Schrander-Stumpel, Connie
AU - Smeets, Hubert
AU - Meinecke, Peter
AU - Malcolm, Sue
AU - Gardner, Anne
AU - Lalande, Marc
AU - Nicholls, Robert D.
AU - Friend, Kathie
AU - Schulze, Astrid
AU - Matthijs, Gert
AU - Kokkonen, Hannaleena
AU - Hilbert, Pascale
AU - Van Maldergem, Lionel
AU - Glover, Guillermo
AU - Carbonell, Pablo
AU - Willems, Patrick
AU - Gillessen-Kaesbach, Gabriele
AU - Horsthemke, Bernhard
N1 - Funding Information:
We thank Dr. A. Surani for a preprint of the paper by Tada et al. (1998) , Dr. D. H. Ledbetter for helpful advice regarding the use of SNRPN methylation analysis for prenatal diagnosis, Dr. R. Trent for work on patient ASID-14 under a National Health and Medical Research Council grant, Drs. R. Sachdev and M. Wilson for collaboration on patient ASID-13, Dr. R. Alpera for collaboration on patient PWSID-03, Dr G. Warne for collaboration on patient PWSID-09, Dr. G. Tariverdian for collaboration on patients PWSID-06 and PWSID-11, Dr. J. da Costa for referring patient PWSID-12, Drs. W. W. M. Hack and E. J. Breslau-Siderius for referring patient PWSID-13, and Dr. K. Bromen for statistical analysis. Part of this work was supported by the Deutsche Forschungsgemeinschaft and by the Human Frontier Science Project.
PY - 1998/7
Y1 - 1998/7
N2 - The Prader-Willi syndrome (PWS) and the Angelman syndrome (AS) are caused by the loss of function of imprinted genes in proximal 15q. In ~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.
AB - The Prader-Willi syndrome (PWS) and the Angelman syndrome (AS) are caused by the loss of function of imprinted genes in proximal 15q. In ~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.
UR - http://www.scopus.com/inward/record.url?scp=0032231460&partnerID=8YFLogxK
U2 - 10.1086/301935
DO - 10.1086/301935
M3 - Journal articles
AN - SCOPUS:0032231460
SN - 0002-9297
VL - 63
SP - 170
EP - 180
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -