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J Med Genet. 2014 Aug;51(8):502-11. doi: 10.1136/jmedgenet-2014-102368. Epub 2014 Jul 4.

Genetic variants within the second intron of the KCNQ1 gene affect CTCF binding and confer a risk of Beckwith-Wiedemann syndrome upon maternal transmission.

Author information

1
Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia INRA, GenPhySE (Génétique, Physiologie et Systèmes d'Elevage), Castanet-Tolosan, France.
2
Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia.
3
Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia University of Melbourne, Parkville, Australia.
4
Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
5
APHP, 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.
6
INRA, GenPhySE (Génétique, Physiologie et Systèmes d'Elevage), Castanet-Tolosan, France.
7
Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia University of Melbourne, Parkville, Australia.

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.

KEYWORDS:

Imprinting; Molecular genetics

PMID:
24996904
DOI:
10.1136/jmedgenet-2014-102368
[Indexed for MEDLINE]

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