TY - JOUR T1 - Rare Copy Number Variants Contribute to Congenital Left-Sided Heart Disease A1 - Hitz, Marc-Phillip A1 - Lemieux-Perreault, Louis-Philippe A1 - Marshall, Christian A1 - Feroz-Zada, Yassamin A1 - Davies, Robbie A1 - Yang, Shi Wei A1 - Lionel, Anath Christopher A1 - D'Amours, Guylaine A1 - Lemyre, Emmanuelle A1 - Cullum, Rebecca A1 - Bigras, Jean-Luc A1 - Thibeault, Maryse A1 - Chetaille, Philippe A1 - Montpetit, Alexandre A1 - Khairy, Paul A1 - Overduin, Bert A1 - Klaassen, Sabine A1 - Hoodless, Pamela A1 - Nemer, Mona A1 - Stewart, Alexandre F. R. A1 - Boerkoel, Cornelius A1 - Scherer, Stephen W. A1 - Richter, Andrea A1 - Dubé, Marie-Pierre A1 - Andelfinger, Gregor Y1 - 2012/09/06 N2 - Author Summary Congenital heart disease (CHD) is the leading malformation among all newborns, and one of the leading causes of morbidity and mortality in Western countries. Left-sided CHD (LS-CHD) encompasses a spectrum ranging from bicuspid aortic valve to aortic stenosis and hypoplastic left heart syndrome with familial clustering. To date, the genetic causes for LS-CHD remain unknown in the majority of patients. To determine the impact of structural genomic variation in multiplex families with LS-CHD, we searched for unique or rare copy number variants present only in affected members of a multiplex family cohort (N total = 464, N affected members = 174 (37.5%)) and absent from 1,582 controls free from LS-CHD. A stringent filter based on in silico prioritization and gene expression analysis during development allowed us to identify genes associated with LS-CHD. Our study revealed 25 new candidate genes for LS-CHD, such as SMC1A, MFAP4, and CTHRC1, and overlap with known syndromic loci. We estimate that unique copy number variants contribute to at least 10% of left-sided CHD cases, with a gene content suggesting broader perturbations of angiogenesis at the base of LS-CHD. JF - PLOS Genetics JA - PLOS Genetics VL - 8 IS - 9 UR - https://doi.org/10.1371/journal.pgen.1002903 SP - e1002903 EP - PB - Public Library of Science M3 - doi:10.1371/journal.pgen.1002903 ER -