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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.

TitleGenetic variants within the second intron of the KCNQ1 gene affect CTCF binding and confer a risk of Beckwith-Wiedemann syndrome upon maternal transmission.
Publication TypeJournal Article
Year of Publication2014
AuthorsDemars, J, Shmela, MEnnuri, Khan, AWaheed, Lee, KSyin, Azzi, S, Dehais, P, Netchine, I, Rossignol, S, Le Bouc, Y, El-Osta, A, Gicquel, C
JournalJ Med Genet
Volume51
Issue8
Pagination502-11
Date Published2014 Aug
ISSN1468-6244
KeywordsBeckwith-Wiedemann Syndrome, Binding Sites, DNA Methylation, Female, Haplotypes, Humans, Introns, KCNQ1 Potassium Channel, Male, Mutation, Repressor Proteins
Abstract

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.

DOI10.1136/jmedgenet-2014-102368
Alternate JournalJ. Med. Genet.
PubMed ID24996904