title: New insights into the pathogenesis of Beckwith-Wiedemann and Silver-Russell syndromes: contribution of small copy number variations to 11p15 imprinting defects.
abstract: The imprinted 11p15 region is organized in two domains, each of them under the control of its own imprinting control region (ICR1 for the IGF2/H19 domain and ICR2 for the KCNQ1OT1/CDKN1C domain). Disruption of 11p15 imprinting results in two fetal growth disorders with opposite phenotypes: the Beckwith-Wiedemann (BWS) and the Silver-Russell (SRS) syndromes. Various 11p15 genetic and epigenetic defects have been demonstrated in BWS and SRS. Among them, isolated DNA methylation defects account for approximately 60% of patients. To investigate whether cryptic copy number variations (CNVs) involving only part of one of the two imprinted domains account for 11p15 isolated DNA methylation defects, we designed a single nucleotide polymorphism array covering the whole 11p15 imprinted region and genotyped 185 SRS or BWS cases with loss or gain of DNA methylation at either ICR1 or ICR2. We describe herein novel small gain and loss CNVs in six BWS or SRS patients, including maternally inherited cis-duplications involving only part of one of the two imprinted domains. We also show that ICR2 deletions do not account for BWS with ICR2 loss of methylation and that uniparental isodisomy involving only one of the two imprinted domains is not a mechanism for SRS or BWS.
authors.affiliation: Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Julie
authors.initials: J
authors.lastname: Demars
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rossignol
authors.forename: Irène
authors.initials: I
authors.lastname: Netchine
authors.forename: Kai Syin
authors.initials: KS
authors.lastname: Lee
authors.forename: Mansur
authors.initials: M
authors.lastname: Shmela
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.forename: Jacques
authors.initials: J
authors.lastname: Weill
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.forename: Salah
authors.initials: S
authors.lastname: Azzi
authors.forename: Patrick
authors.initials: P
authors.lastname: Callier
authors.forename: Josette
authors.initials: J
authors.lastname: Lucas
authors.forename: Christèle
authors.initials: C
authors.lastname: Dubourg
authors.forename: Joris
authors.initials: J
authors.lastname: Andrieux
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Bouc
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
authors.forename: Christine
authors.initials: C
authors.lastname: Gicquel
mesh_terms: D000328:Adult; D001483:Base Sequence; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D056730:Silver-Russell Syndrome / Q000235:genetics*