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Exhaustive methylation analysis revealed uneven profiles of methylation at IGF2/ICR1/H19 11p15 loci in Russell Silver syndrome
  1. Salah Azzi1,2,3,4,
  2. Virginie Steunou1,
  3. Jörg Tost5,
  4. Sylvie Rossignol1,2,3,
  5. Nathalie Thibaud3,
  6. Cristina Das Neves3,
  7. Marilyne Le Jule3,
  8. Walid Abi Habib1,2,3,
  9. Annick Blaise1,2,
  10. Yves Koudou6,7,
  11. Florence Busato4,
  12. Yves Le Bouc1,2,3,
  13. Irène Netchine1,2,3
  1. 1INSERM, UMR_S 938, CDR Saint-Antoine, Paris, France
  2. 2Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France
  3. 3Department of Pediatric Endocrinology, APHP, Armand Trousseau Hospital, Paris, France
  4. 4Epigenetics Programme, The Babraham Institute, Cambridge, UK
  5. 5Laboratory for Epigenetics and Environment (LEE), National Genotyping Center, CEA—Institute of Genomics, Evry, France
  6. 6INSERM, Centre for research in Epidemiology and Population Health (CESP), U1018, Lifelong epidemiology of obesity, diabetes and renal disease team, Villejuif, France
  7. 7Paris-Sud University, UMRS 1018, Villejuif, France
  1. Correspondence to Dr Irène Netchine, INSERM, UMR_S 938, CDR Saint-Antoine, 26 Avenue du Dr Arnold NETTER, Paris 75012, France; irene.netchine{at}


Background The structural organisation of the human IGF2/ICR1/H19 11p15 domain is very complex, and the mechanisms underlying its regulation are poorly understood. The Imprinted Center Region 1 (ICR1) contains seven binding sites for the zinc-finger protein CTCF (CBS: CTCF Binding Sites); three additional differentially methylated regions (DMR) are located at the H19 promoter (H19DMR) and two in the IGF2 gene (DMR0 and DMR2), respectively. Loss of imprinting at the IGF2/ICR1/H19 domain results in two growth disorders with opposite phenotypes: Beckwith–Wiedemann syndrome and Russell Silver syndrome (RSS). Despite the IGF2/ICR1/H19 locus being widely studied, the extent of hypomethylation across the domain remains not yet addressed in patients with RSS.

Methods We assessed a detailed investigation of the methylation status of the 11p15 ICR1 CBS1-7, IGF2DMR0 and H19DMR (H19 promoter) in a population of controls (n=50) and RSS carrying (n=104) or not (n=65) carrying a hypomethylation at the 11p15 ICR1 region.

Results The methylation indexes (MI) were balanced at all regions in the control population and patients with RSS without any as yet identified molecular anomaly. Interestingly, patients with RSS with ICR1 hypomethylation showed uneven profiles of methylation among the CBSs and DMRs. Furthermore, normal MIs at CBS1 and CBS7 were identified in 9% of patients.

Conclusions The hypomethylation does not spread equally throughout the IGF2/ICR1/H19 locus, and some loci could have normal MI, which may lead to underdiagnosis of patients with RSS with ICR1 hypomethylation. The uneven pattern of methylation suggests that some CBSs may play different roles in the tridimensional chromosomal looping regulation of this locus.

  • Imprinting Disorders
  • 11p15 region
  • Russell Silver Syndrome
  • IGF2/H19 domain
  • Growth retardation

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