학술논문
De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot.
Document Type
Article
Author
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.
Source
Subject
*TETRALOGY of Fallot
*CONGENITAL heart disease
*GENE expression
*GENETIC mutation
*CLINICAL trials
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Language
ISSN
1061-4036
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. [ABSTRACT FROM AUTHOR]