title: Sporadic imprinting defects in Prader-Willi syndrome and Angelman syndrome: implications for imprint-switch models, genetic counseling, and prenatal diagnosis.
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.
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Buiting
authors.forename: B
authors.initials: B
authors.lastname: Dittrich
authors.forename: S
authors.initials: S
authors.lastname: Gross
authors.forename: C
authors.initials: C
authors.lastname: Lich
authors.forename: C
authors.initials: C
authors.lastname: Färber
authors.forename: T
authors.initials: T
authors.lastname: Buchholz
authors.forename: E
authors.initials: E
authors.lastname: Smith
authors.forename: A
authors.initials: A
authors.lastname: Reis
authors.forename: J
authors.initials: J
authors.lastname: Bürger
authors.forename: M M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: U
authors.initials: U
authors.lastname: Barth-Witte
authors.forename: B
authors.initials: B
authors.lastname: Janssen
authors.forename: D
authors.initials: D
authors.lastname: Abeliovich
authors.forename: I
authors.initials: I
authors.lastname: Lerer
authors.forename: A M
authors.initials: AM
authors.lastname: van den Ouweland
authors.forename: D J
authors.initials: DJ
authors.lastname: Halley
authors.forename: C
authors.initials: C
authors.lastname: Schrander-Stumpel
authors.forename: H
authors.initials: H
authors.lastname: Smeets
authors.forename: P
authors.initials: P
authors.lastname: Meinecke
authors.forename: S
authors.initials: S
authors.lastname: Malcolm
authors.forename: A
authors.initials: A
authors.lastname: Gardner
authors.forename: M
authors.initials: M
authors.lastname: Lalande
authors.forename: R D
authors.initials: RD
authors.lastname: Nicholls
authors.forename: K
authors.initials: K
authors.lastname: Friend
authors.forename: A
authors.initials: A
authors.lastname: Schulze
authors.forename: G
authors.initials: G
authors.lastname: Matthijs
authors.forename: H
authors.initials: H
authors.lastname: Kokkonen
authors.forename: P
authors.initials: P
authors.lastname: Hilbert
authors.forename: L
authors.initials: L
authors.lastname: Van Maldergem
authors.forename: G
authors.initials: G
authors.lastname: Glover
authors.forename: P
authors.initials: P
authors.lastname: Carbonell
authors.forename: P
authors.initials: P
authors.lastname: Willems
authors.forename: G
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: B
authors.initials: B
authors.lastname: Horsthemke
mesh_terms: D017204:Angelman Syndrome / Q000235:genetics*; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D005817:Genetic Counseling; D005819:Genetic Markers / Q000235:genetics; D018392:Genomic Imprinting / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011218:Prader-Willi Syndrome / Q000235:genetics*; D011296:Prenatal Diagnosis; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D005819:Genetic Markers