title: 11p15 ICR1 Partial Deletions Associated with IGF2/H19 DMR Hypomethylation and Silver-Russell Syndrome.
abstract: The 11p15 region harbors the IGF2/H19 imprinted domain, implicated in fetal and postnatal growth. Silver-Russell syndrome (SRS) is characterized by fetal and postnatal growth failure, and is caused principally by hypomethylation of the 11p15 imprinting control region 1 (ICR1). However, the mechanisms leading to ICR1 hypomethylation remain unknown. Maternally inherited genetic defects affecting the ICR1 domain have been associated with ICR1 hypermethylation and Beckwith-Wiedemann syndrome (an overgrowth syndrome, the clinical and molecular mirror of SRS), and paternal deletions of IGF2 enhancers have been detected in four SRS patients. However, no paternal deletions of ICR1 have ever been associated with hypomethylation of the IGF2/H19 domain in SRS. We screened for new genetic defects within the ICR1 in a cohort of 234 SRS patients with hypomethylated IGF2/H19 domain. We report deletions close to the boundaries of ICR1 on the paternal allele in one familial and two sporadic cases of SRS with ICR1 hypomethylation. These deletions are associated with hypomethylation of the remaining CBS, and decreased IGF2 expression. These results suggest that these regions are most likely required to maintain methylation after fertilization. We estimate these anomalies to occur in about 1% of SRS cases with ICR1 hypomethylation.
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.|AP-HP, Hôpital Trousseau, Service d'explorations fonctionnelles endocriniennes, Paris, 75571, 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.|AP-HP, Hôpital Trousseau, Service d'explorations fonctionnelles endocriniennes, Paris, 75571, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Brioude
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.|AP-HP, Hôpital Trousseau, Service d'explorations fonctionnelles endocriniennes, Paris, 75571, France.|Epigenetics Programme, The Babraham Institute, Cambridge, UK.
authors.forename: Salah
authors.initials: S
authors.lastname: Azzi
authors.affiliation: MAGIC Foundation, RSS/SGA Research and Education Fund, Oak Park, Illinois.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Salem
authors.affiliation: AP-HP, Hôpital Trousseau, Service d'explorations fonctionnelles endocriniennes, Paris, 75571, France.
authors.forename: Cristina
authors.initials: C
authors.lastname: Das Neves
authors.affiliation: Centre Hospitalier Intercommunal, Service de Pédiatrie, Poissy, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Personnier
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: 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.|AP-HP, Hôpital Trousseau, Service d'explorations fonctionnelles endocriniennes, Paris, 75571, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Bouc
authors.affiliation: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Madeleine D
authors.initials: MD
authors.lastname: Harbison
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.|AP-HP, Hôpital Trousseau, Service d'explorations fonctionnelles endocriniennes, Paris, 75571, France.
authors.forename: Irene
authors.initials: I
authors.lastname: Netchine
mesh_terms: D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11; D019175:DNA Methylation; D005260:Female; D005347:Fibroblasts; D015870:Gene Expression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008297:Male; D010375:Pedigree; D062085:RNA, Long Noncoding / Q000235:genetics*; D017384:Sequence Deletion; D056730:Silver-Russell Syndrome / Q000235:genetics*
chemical_list: C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D007335:Insulin-Like Growth Factor II
keywords: IGF2/H19 imprinted domain; Silver-Russell syndrome; deletions; hypomethylation; imprinting control region 1