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Contribution of Global Rare Copy-Number Variants to the Risk of Sporadic Congenital Heart Disease

Lookup NU author(s): Rachel Soemedi, Dr Ian Wilson, Dr Rebecca Darlay, Dr Ana TopfORCiD, Dr Simon Zwolinski, Valentina Mamasoula, Dr Thahira Rahman, Dr Darroch Hall, Dr Mauro Santibanez Koref, Professor Heather Cordell, Professor Judith Goodship, Professor Bernard Keavney


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Previous studies have shown that copy-number variants (CNVs) contribute to the risk of complex developmental phenotypes. However, the contribution of global CNV burden to the risk of sporadic congenital heart disease (CHD) remains incompletely defined. We generated genome-wide CNV data by using Illumina 660W-Quad SNP arrays in 2,256 individuals with CHD, 283 trio CHD-affected families, and 1,538 controls. We found association of rare genic deletions with CHD risk (odds ratio [OR] = 1.8, p = 0.0008). Rare deletions in study participants with CHI) had higher gene content (p = 0.001) with higher haploinsufficiency scores (p = 0.03) than they did in controls, and they were enriched with Wnt-signaling genes (p = 1 x 10(-5)). Recurrent 15q11.2 deletions were associated with CHD risk (OR = 8.2, p = 0.02). Rare de novo CNVs were observed in similar to 5% of CHD trios; 10 out of 11 occurred on the paternally transmitted chromosome (p = 0.01). Some of the rare de novo CNVs spanned genes known to be involved in heart development (e.g., HAND2 and (VAS). Rare genic deletions contribute similar to 4% of the population-attributable risk of sporadic CHI). Second to previously described CNVs at 1q21.1, deletions at 15q11.2 and those implicating Wnt signaling are the most significant contributors to the risk of sporadic CHD. Rare de novo CNVs identified in CHI) trios exhibit paternal origin bias.

Publication metadata

Author(s): Soemedi R, Wilson IJ, Bentham J, Darlay R, Topf A, Zelenika D, Cosgrove C, Setchfield K, Thornborough C, Granados-Riveron J, Blue GM, Breckpot J, Hellens S, Zwolinkski S, Glen E, Mamasoula C, Rahman TJ, Hall D, Rauch A, Devriendt K, Gewillig M, O' Sullivan J, Winlaw DS, Bu'Lock F, Brook JD, Bhattacharya S, Lathrop M, Santibanez-Koref M, Cordell HJ, Goodship JA, Keavney BD

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2012

Volume: 91

Issue: 3

Pages: 489-501

Print publication date: 07/09/2012

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2012.08.003


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Funder referenceFunder name
National Institute for Health Research through the Northumberland, Tyne, and Wear Comprehensive Local Research Network
Wellcome Trust
British Heart Foundation (BHF)
Federated Foundation
Heart Research UK
IMF personal chairs
HEALTH-F2-2008-223040European Community