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PMID: 22969434 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

PLoS genetics ·Vol. 8 ·No. 9 ·2012-09-00 ·Pages e1002903

Hitz MP, Lemieux-Perreault LP, Marshall C, Feroz-Zada Y, Davies R, Yang SW, Lionel AC, D'Amours G, Lemyre E, Cullum R, Bigras JL, Thibeault M, Chetaille P, Montpetit A, Khairy P, Overduin B, Klaassen S, Hoodless P, Awadalla P, Hussin J, Idaghdour Y, Nemer M, Stewart AF, Boerkoel C, Scherer SW, Richter A, Dubé MP, 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.

MeSH Terms
Adolescent Adult Aged Aged, 80 and over Animals Child Child, Preschool DNA Copy Number Variations Family Female Heart/embryology Heart Defects, Congenital/genetics Humans Male Mice Middle Aged Myocardium/metabolism Neovascularization, Physiologic Young Adult
Authors & Affiliations
28 authors, click to expand affiliations / ORCID
Hitz Marc-Phillip
Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte Justine, Université de Montréal, Montréal, Québec, Canada.
Lemieux-Perreault Louis-Philippe
Marshall Christian
Feroz-Zada Yassamin
Davies Robbie
Yang Shi Wei
Lionel Anath Christopher
D'Amours Guylaine
Lemyre Emmanuelle
Cullum Rebecca
Bigras Jean-Luc
Thibeault Maryse
Chetaille Philippe
Montpetit Alexandre
Khairy Paul
Overduin Bert
Klaassen Sabine
Hoodless Pamela
Awadalla Philip
Hussin Julie
Idaghdour Youssef
Nemer Mona
Stewart Alexandre F R
Boerkoel Cornelius
Scherer Stephen W
Richter Andrea
Dubé Marie-Pierre
Andelfinger Gregor
Conflict of Interest

The authors have declared that no competing interests exist.

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Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1002903
Published
2012-09-00
Epub
2012-00-06
Pages
e1002903
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC3435243
Subset
IM
Grants
Wellcome Trust · 095908 · United Kingdom
CIHR · Canada
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1371/journal.pgen.1002903 PMC Full Text View journal details
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