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- Title
De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot.
- Authors
Greenway, Steven C; Pereira, Alexandre C; Lin, Jennifer C; DePalma, Steven R; Israel, Samuel J; Mesquita, Sonia M; Ergul, Emel; Conta, Jessie H; Korn, Joshua M; McCarroll, Steven A; Gorham, Joshua M; Gabriel, Stacey; Altshuler, David M; Quintanilla-Dieck, Maria de Lourdes; Artunduaga, Maria Alexandra; Eavey, Roland D; Plenge, Robert M; Shadick, Nancy A; Weinblatt, Michael E; De Jager, Philip L; Hafler, David A; Breitbart, Roger E; Seidman, Jonathan G; Seidman, Christine E
- Abstract
Tetralogy of Fallot (TOF), the most common severe congenital heart malformation, occurs sporadically, without other anomaly, and from unknown cause in 70% of cases. Through a genome-wide survey of 114 subjects with TOF and their unaffected parents, we identified 11 de novo copy number variants (CNVs) that were absent or extremely rare (<0.1%) in 2,265 controls. We then examined a second, independent TOF cohort (n = 398) for additional CNVs at these loci. We identified CNVs at chromosome 1q21.1 in 1% (5/512, P = 0.0002, OR = 22.3) of nonsyndromic sporadic TOF cases. We also identified recurrent CNVs at 3p25.1, 7p21.3 and 22q11.2. CNVs in a single subject with TOF occurred at six loci, two that encode known (NOTCH1, JAG1) disease-associated genes. Our findings predict that at least 10% (4.5-15.5%, 95% confidence interval) of sporadic nonsyndromic TOF cases result from de novo CNVs and suggest that mutations within these loci might be etiologic in other cases of TOF.
- Publication
Nature genetics, 2009, Vol 41, Issue 8, p931
- ISSN
1546-1718
- Publication type
Journal Article
- DOI
10.1038/ng.415