De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot.
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.
Greenway
Steven C
SC
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
Pereira
Alexandre C
AC
Lin
Jennifer C
JC
DePalma
Steven R
SR
Israel
Samuel J
SJ
Mesquita
Sonia M
SM
Ergul
Emel
E
Conta
Jessie H
JH
Korn
Joshua M
JM
McCarroll
Steven A
SA
Gorham
Joshua M
JM
Gabriel
Stacey
S
Altshuler
David M
DM
Quintanilla-Dieck
Maria de Lourdes
Mde L
Artunduaga
Maria Alexandra
MA
Eavey
Roland D
RD
Plenge
Robert M
RM
Shadick
Nancy A
NA
Weinblatt
Michael E
ME
De Jager
Philip L
PL
Hafler
David A
DA
Breitbart
Roger E
RE
Seidman
Jonathan G
JG
Seidman
Christine E
CE
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