De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot

• Published in: Nature genetics Vol. 41; no. 8; pp. 931 - 935
• Main Authors: Seidman, Christine E, 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, de Lourdes Quintanilla-Dieck, Maria, 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-08-2009; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cardiology. Vascular system; Cardiovascular disease; Child, Preschool; Chromosomes, Human, Pair 1 - genetics; Chromosomes, Human, Pair 3 - genetics; Congenital heart diseases. Malformations of the aorta, pulmonary vessels and vena cava; Data analysis; Fundamental and applied biological sciences. Psychology; Gene Dosage; Gene Expression Regulation; Gene Function; Genes; Genetic aspects; Genetic Variation; Genetics of eukaryotes. Biological and molecular evolution; Heart; Heart Ventricles - metabolism; Human Genetics; Humans; letter; Medical sciences; Mutation; Phenotype; Risk factors; Studies; Tetralogy of Fallot; Tetralogy of Fallot - genetics; Tetralogy of Fallot - pathology; United States; Variant; Gene; Sporadic; Copy number; Heart disease; Fallot tetralogy; Cardiovascular disease; Identification; Locus; Congenital disease; De novo
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.415

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.