RT Journal Article SR Electronic T1 Genetic variants within the second intron of the KCNQ1 gene affect CTCF binding and confer a risk of Beckwith–Wiedemann syndrome upon maternal transmission JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 502 OP 511 DO 10.1136/jmedgenet-2014-102368 VO 51 IS 8 A1 Demars, Julie A1 Shmela, Mansur Ennuri A1 Khan, Abdul Waheed A1 Lee, Kai Syin A1 Azzi, Salah A1 Dehais, Patrice A1 Netchine, Irène A1 Rossignol, Sylvie A1 Le Bouc, Yves A1 El-Osta, Assam A1 Gicquel, Christine YR 2014 UL http://jmg.bmj.com/content/51/8/502.abstract AB 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.