Letter abstract

Nature Genetics 41, 931 - 935 (2009)
Published online: 13 July 2009 | doi:10.1038/ng.415

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

Steven C Greenway1, Alexandre C Pereira2, Jennifer C Lin1, Steven R DePalma1, Samuel J Israel1, Sonia M Mesquita2, Emel Ergul3, Jessie H Conta3, Joshua M Korn1,4, Steven A McCarroll1,4, Joshua M Gorham1, Stacey Gabriel4, David M Altshuler1,4, Maria de Lourdes Quintanilla-Dieck1,5, Maria Alexandra Artunduaga1,5, Roland D Eavey5, Robert M Plenge4,6, Nancy A Shadick6, Michael E Weinblatt6, Philip L De Jager4,7, David A Hafler4,7, Roger E Breitbart3, Jonathan G Seidman1,9 & Christine E Seidman1,8,9


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.

  1. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
  2. Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo Medical School, São Paulo, Brazil.
  3. Department of Cardiology, Children's Hospital, Boston, Massachusetts, USA.
  4. The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  5. Department of Otology and Laryngology, Massachusetts Eye & Ear Infirmary, Boston, Massachusetts, USA.
  6. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA.
  7. Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
  8. Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
  9. These authors contributed equally to this study.

Correspondence to: Christine E Seidman1,8,9
e-mail: cseidman@genetics.med.harvard.edu