title: 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.
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.
authors.affiliation: 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.
authors.forename: Walid
authors.initials: W
authors.lastname: Abi Habib
authors.affiliation: 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.
authors.forename: Salah
authors.initials: S
authors.lastname: Azzi
authors.affiliation: 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.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Brioude
authors.affiliation: INSERM, UMR_S 938, CDR Saint-Antoine, Paris F-75012, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Steunou
authors.affiliation: Pediatric Endocrinology, APHP, Armand Trousseau Hospital, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Thibaud
authors.affiliation: Pediatric Endocrinology, APHP, Armand Trousseau Hospital, Paris, France.
authors.forename: Cristina
authors.initials: C
authors.lastname: Das Neves
authors.affiliation: Pediatric Endocrinology, APHP, Armand Trousseau Hospital, Paris, France.
authors.forename: Marilyne
authors.initials: M
authors.lastname: Le Jule
authors.affiliation: 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.
authors.forename: Sandra
authors.initials: S
authors.lastname: Chantot-Bastaraud
authors.affiliation: Département de Génétique, CRICM UPMC INSERM UMR_S975/CNRS UMR 7225, GH Pitié-Salpêtrière, APHP, Paris, France.
authors.forename: Boris
authors.initials: B
authors.lastname: Keren
authors.affiliation: University Paris Descartes-Sorbonne, Paris Cité, Institut Imagine, INSERM U1163, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.affiliation: University Paris Descartes-Sorbonne, Paris Cité, Institut Imagine, INSERM U1163, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Michot
authors.affiliation: 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.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Service de Génétique Médicale-CLAD Ouest, Hôpital Sud, CHU Rennes, Rennes, France and.
authors.forename: Laurent
authors.initials: L
authors.lastname: Pasquier
authors.affiliation: Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
authors.forename: Christine
authors.initials: C
authors.lastname: Gicquel
authors.affiliation: INSERM, UMR_S 938, CDR Saint-Antoine, Paris F-75012, France, Pediatric Endocrinology, APHP, Armand Trousseau Hospital, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rossignol
authors.affiliation: 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.
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Bouc
authors.affiliation: 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.
authors.forename: Irène
authors.initials: I
authors.lastname: Netchine
mesh_terms: D001483:Base Sequence; D001506:Beckwith-Wiedemann Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D001665:Binding Sites; D016022:Case-Control Studies; D002880:Chromosomes, Human, Pair 11; D019175:DNA Methylation; D005260:Female; D005787:Gene Frequency; D018392:Genomic Imprinting; D006579:Heterozygote; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008297:Male; D009154:Mutation; D059372:Nucleotide Motifs; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D010375:Pedigree; D010641:Phenotype; D062085:RNA, Long Noncoding / Q000235:genetics*; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D017384:Sequence Deletion
chemical_list: C094335:H19 long non-coding RNA; D050814:Octamer Transcription Factor-3; D062085:RNA, Long Noncoding; D055748:SOXB1 Transcription Factors; D007335:Insulin-Like Growth Factor II