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

Nat Genet. 2009 Aug;41(8):931-5. doi: 10.1038/ng.415. Epub 2009 Jul 13.


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 types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child, Preschool
  • Chromosomes, Human, Pair 1 / genetics
  • Chromosomes, Human, Pair 3 / genetics
  • Gene Dosage*
  • Gene Expression Regulation
  • Genetic Variation*
  • Heart Ventricles / metabolism
  • Humans
  • Phenotype
  • Tetralogy of Fallot / genetics*
  • Tetralogy of Fallot / pathology