New insights into the pathogenesis of Beckwith-Wiedemann and Silver-Russell syndromes: contribution of small copy number variations to 11p15 imprinting defects.

Julie Demars (1) , Sylvie Rossignol (2) , Irène Netchine (2) , Kai Syin Lee (1) , Mansur Shmela (1) , Laurence Faivre (3) , Jacques Weill (4) , Sylvie Odent (5) , Salah Azzi (2) , Patrick Callier (6) , Josette Lucas (7) , Christèle Dubourg (8) , Joris Andrieux (9) , Yves Le Bouc (2) , Assam El-Osta (1) , Christine Gicquel (1)

1 Epigenetics in Human Health and Disease
2 UMRS893 - Centre de Recherche Saint-Antoine
3 Department of Experimental Cardiology
4 Service d'endocrinologie pédiatrique [CHU Lille]
5 Service de génétique clinique [Rennes]
6 Laboratoire de cytogénétique (CHU de Dijon)
7 Service de Cytogénétique et de Biologie Cellulaire
8 Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes]
9 Laboratoire de Génétique Clinique

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.

Mots clés: fetal growth; genomic imprinting; copy number variation; 11p15 region; Silver-Russell syndrome; Beckwith-Wiedemann syndrome; fetal growth.

Domaines: Génétique; Biologie du développement

Julie Demars, Sylvie Rossignol, Irène Netchine, Kai Syin Lee, Mansur Shmela, et al.. New insights into the pathogenesis of Beckwith-Wiedemann and Silver-Russell syndromes: contribution of small copy number variations to 11p15 imprinting defects.. Human Mutation, 2011, 32 (10), pp.1171-82. ⟨10.1002/humu.21558⟩. ⟨inserm-00610827⟩