title: Rare copy number variants contribute to congenital left-sided heart disease.
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.
authors.affiliation: Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte Justine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Marc-Phillip
authors.initials: MP
authors.lastname: Hitz
authors.forename: Louis-Philippe
authors.initials: LP
authors.lastname: Lemieux-Perreault
authors.forename: Christian
authors.initials: C
authors.lastname: Marshall
authors.forename: Yassamin
authors.initials: Y
authors.lastname: Feroz-Zada
authors.forename: Robbie
authors.initials: R
authors.lastname: Davies
authors.forename: Shi Wei
authors.initials: SW
authors.lastname: Yang
authors.forename: Anath Christopher
authors.initials: AC
authors.lastname: Lionel
authors.forename: Guylaine
authors.initials: G
authors.lastname: D'Amours
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Lemyre
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cullum
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Bigras
authors.forename: Maryse
authors.initials: M
authors.lastname: Thibeault
authors.forename: Philippe
authors.initials: P
authors.lastname: Chetaille
authors.forename: Alexandre
authors.initials: A
authors.lastname: Montpetit
authors.forename: Paul
authors.initials: P
authors.lastname: Khairy
authors.forename: Bert
authors.initials: B
authors.lastname: Overduin
authors.forename: Sabine
authors.initials: S
authors.lastname: Klaassen
authors.forename: Pamela
authors.initials: P
authors.lastname: Hoodless
authors.forename: Philip
authors.initials: P
authors.lastname: Awadalla
authors.forename: Julie
authors.initials: J
authors.lastname: Hussin
authors.forename: Youssef
authors.initials: Y
authors.lastname: Idaghdour
authors.forename: Mona
authors.initials: M
authors.lastname: Nemer
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
authors.forename: Cornelius
authors.initials: C
authors.lastname: Boerkoel
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.forename: Andrea
authors.initials: A
authors.lastname: Richter
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dubé
authors.forename: Gregor
authors.initials: G
authors.lastname: Andelfinger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D005190:Family; D005260:Female; D006321:Heart / Q000196:embryology; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D018919:Neovascularization, Physiologic; D055815:Young Adult