title: De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot.
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.
authors: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors: Steven C
authors: SC
authors: Greenway
authors: Alexandre C
authors: AC
authors: Pereira
authors: Jennifer C
authors: JC
authors: Lin
authors: Steven R
authors: SR
authors: DePalma
authors: Samuel J
authors: SJ
authors: Israel
authors: Sonia M
authors: SM
authors: Mesquita
authors: Emel
authors: E
authors: Ergul
authors: Jessie H
authors: JH
authors: Conta
authors: Joshua M
authors: JM
authors: Korn
authors: Steven A
authors: SA
authors: McCarroll
authors: Joshua M
authors: JM
authors: Gorham
authors: Stacey
authors: S
authors: Gabriel
authors: David M
authors: DM
authors: Altshuler
authors: Maria de Lourdes
authors: Mde L
authors: Quintanilla-Dieck
authors: Maria Alexandra
authors: MA
authors: Artunduaga
authors: Roland D
authors: RD
authors: Eavey
authors: Robert M
authors: RM
authors: Plenge
authors: Nancy A
authors: NA
authors: Shadick
authors: Michael E
authors: ME
authors: Weinblatt
authors: Philip L
authors: PL
authors: De Jager
authors: David A
authors: DA
authors: Hafler
authors: Roger E
authors: RE
authors: Breitbart
authors: Jonathan G
authors: JG
authors: Seidman
authors: Christine E
authors: CE
authors: Seidman
mesh_terms: D002675:Child, Preschool; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D018628:Gene Dosage; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D010641:Phenotype; D013771:Tetralogy of Fallot / Q000235:genetics* / Q000473:pathology