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Hum Mol Genet. 2014 Nov 1;23(21):5763-73. doi: 10.1093/hmg/ddu290. Epub 2014 Jun 10.

Extensive investigation of the IGF2/H19 imprinting control region reveals novel OCT4/SOX2 binding site defects associated with specific methylation patterns in Beckwith-Wiedemann syndrome.

Author information

1
INSERM, UMR_S 938, CDR Saint-Antoine, Paris F-75012, France, Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris F-75012, France, Pediatric Endocrinology, APHP, Armand Trousseau Hospital, Paris, France.
2
INSERM, UMR_S 938, CDR Saint-Antoine, Paris F-75012, France.
3
Pediatric Endocrinology, APHP, Armand Trousseau Hospital, Paris, France.
4
INSERM U933, Service de Génétique et D'Embryologie Médicales, Paris 75571, France, AP-HP, Hôpital Trousseau, Service de Génétique et D'Embryologie Médicales, Paris 75571, France.
5
Département de Génétique, CRICM UPMC INSERM UMR_S975/CNRS UMR 7225, GH Pitié-Salpêtrière, APHP, Paris, France.
6
University Paris Descartes-Sorbonne, Paris Cité, Institut Imagine, INSERM U1163, Hôpital Necker-Enfants Malades, Paris, France.
7
Service de Génétique, Centre de Référence des Anomalies du Développement Centre-Est, Hospices Civils de Lyon, Bron, France, INSERM U1028 UMR CNRS 5292, UCBL, CRNL TIGER Team, Lyon, France.
8
Service de Génétique Médicale-CLAD Ouest, Hôpital Sud, CHU Rennes, Rennes, France and.
9
Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
10
INSERM, UMR_S 938, CDR Saint-Antoine, Paris F-75012, France, Pediatric Endocrinology, APHP, Armand Trousseau Hospital, Paris, France.
11
INSERM, UMR_S 938, CDR Saint-Antoine, Paris F-75012, France, Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris F-75012, France, Pediatric Endocrinology, APHP, Armand Trousseau Hospital, Paris, France, irene.netchine@trs.aphp.fr.

Abstract

Isolated gain of methylation (GOM) at the IGF2/H19 imprinting control region 1 (ICR1) accounts for about 10% of patients with BWS. A subset of these patients have genetic defects within ICR1, but the frequency of these defects has not yet been established in a large cohort of BWS patients with isolated ICR1 GOM. Here, we carried out a genetic analysis in a large cohort of 57 BWS patients with isolated ICR1 GOM and analyzed the methylation status of the entire domain. We found a new point mutation in two unrelated families and a 21 bp deletion in another unrelated child, both of which were maternally inherited and affected the OCT4/SOX2 binding site in the A2 repeat of ICR1. Based on data from this and previous studies, we estimate that cis genetic defects account for about 20% of BWS patients with isolated ICR1 GOM. Methylation analysis at eight loci of the IGF2/H19 domain revealed that sites surrounding OCT4/SOX2 binding site mutations were fully methylated and methylation indexes declined as a function of distance from these sites. This was not the case in BWS patients without genetic defects identified. Thus, GOM does not spread uniformly across the IGF2/H19 domain, suggesting that OCT4/SOX2 protects against methylation at local sites. These findings add new insights to the mechanism of the regulation of the ICR1 domain. Our data show that mutations and deletions within ICR1 are relatively common. Systematic identification is therefore necessary to establish appropriate genetic counseling for BWS patients with isolated ICR1 GOM.

PMID:
24916376
DOI:
10.1093/hmg/ddu290
[Indexed for MEDLINE]

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