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Rare copy number variants contribute to congenital left-sided heart disease

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Item Type:Article
Title:Rare copy number variants contribute to congenital left-sided heart disease
Creators Name:Hitz, M.P. and Lemieux-Perreault, L.P. and Marshall, C. and Feroz-Zada, Y. and Davies, R. and Yang, S.W. and Lionel, A.C. and D'Amours, G. and Lemyre, E. and Cullum, R. and Bigras, J.L. and Thibeault, M. and Chetaille, P. and Montpetit, A. and Khairy, P. and Overduin, B. and Klaassen, S. and Hoodless, P. and Awadalla, P. and Hussin, J. and Idaghdour, Y. and Nemer, M. and Stewart, A.F. and Boerkoel, C. and Scherer, S.W. and Richter, A. and Dube, M.P. and Andelfinger, G.
Abstract:Left-sided congenital heart disease (CHD) encompasses a spectrum of malformations that range from bicuspid aortic valve to hypoplastic left heart syndrome. It contributes significantly to infant mortality and has serious implications in adult cardiology. Although left-sided CHD is known to be highly heritable, the underlying genetic determinants are largely unidentified. In this study, we sought to determine the impact of structural genomic variation on left-sided CHD and compared multiplex families (464 individuals with 174 affecteds (37.5%) in 59 multiplex families and 8 trios) to 1,582 well-phenotyped controls. 73 unique inherited or de novo CNVs in 54 individuals were identified in the left-sided CHD cohort. After stringent filtering, our gene inventory reveals 25 new candidates for LS-CHD pathogenesis, such as SMC1A, MFAP4, and CTHRC1, and overlaps with several known syndromic loci. Conservative estimation examining the overlap of the prioritized gene content with CNVs present only in affected individuals in our cohort implies a strong effect for unique CNVs in at least 10% of left-sided CHD cases. Enrichment testing of gene content in all identified CNVs showed a significant association with angiogenesis. In this first family-based CNV study of left-sided CHD, we found that both co-segregating and de novo events associate with disease in a complex fashion at structural genomic level. Often viewed as an anatomically circumscript disease, a subset of left-sided CHD may in fact reflect more general genetic perturbations of angiogenesis and/or vascular biology.
Keywords:Congenital Heart Defects, DNA Copy Number Variations, Heart, Myocardium, Physiologic Neovascularization, Animals, Mice
Source:PLoS Genetics
ISSN:1553-7404
Publisher:Public Library of Science (U.S.A.)
Volume:8
Number:9
Page Range:e1002903
Date:6 September 2012
Official Publication:https://doi.org/10.1371/journal.pgen.1002903
PubMed:View item in PubMed

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