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Genetic variants within the second intron of the KCNQ1 gene affect CTCF binding and confer a risk of Beckwith–Wiedemann syndrome upon maternal transmission
  1. Julie Demars1,2,
  2. Mansur Ennuri Shmela1,3,
  3. Abdul Waheed Khan1,4,
  4. Kai Syin Lee1,
  5. Salah Azzi5,
  6. Patrice Dehais2,
  7. Irène Netchine5,
  8. Sylvie Rossignol5,
  9. Yves Le Bouc5,
  10. Assam El-Osta1,3,4,
  11. Christine Gicquel1,3
  1. 1Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
  2. 2INRA, GenPhySE (Génétique, Physiologie et Systèmes d'Elevage), Castanet-Tolosan, France
  3. 3Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia
  4. 4University of Melbourne, Parkville, Australia
  5. 5APHP, Armand Trousseau Hôpital, Pediatric Endocrinology, INSERM, UMR_S 938, CDR Saint-Antoine, F-75012, Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France
  1. Correspondence to Dr Christine Gicquel, Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; christine.gicquel{at}


Background Disruption of 11p15 imprinting results in two fetal growth disorders with opposite phenotypes: the Beckwith–Wiedemann (BWS; MIM 130650) and the Silver–Russell (SRS; MIM 180860) syndromes. DNA methylation defects account for 60% of BWS and SRS cases and, in most cases, occur without any identified mutation in a cis-acting regulatory sequence or a trans-acting factor.

Methods We investigated whether 11p15 cis-acting sequence variants account for primary DNA methylation defects in patients with SRS and BWS with loss of DNA methylation at ICR1 and ICR2, respectively.

Results We identified a 4.5 kb haplotype that, upon maternal transmission, is associated with a risk of ICR2 loss of DNA methylation in patients with BWS. This novel region is located within the second intron of the KCNQ1 gene, 170 kb upstream of the ICR2 imprinting centre and encompasses two CTCF binding sites. We showed that, within the 4.5 kb region, two SNPs (rs11823023 and rs179436) affect CTCF occupancy at DNA motifs flanking the CTCF 20 bp core motif.

Conclusions This study shows that genetic variants confer a risk of DNA methylation defect with a parent-of-origin effect and highlights the crucial role of CTCF for the regulation of genomic imprinting of the CDKN1C/KCNQ1 domain.

  • Imprinting
  • Molecular genetics

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