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.

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We gratefully acknowledge the participation of families. We also thank C. Sougnez and M. Parkin for technical assistance and R. Geggel for supplying TOF images. This work was supported by grants from the Howard Hughes Medical Institute (C.E.S.), US National Institutes of Health (to C.E.S., J.G.S. and R.E.B. and to the Broad Institute (National Center for Research Resources)), Pediatric Scientist Development Program (S.C.G.) and Sarnoff Cardiovascular Research Foundation (J.C.L.). Multiple sclerosis controls were genotyped in collaboration with Affymetrix, Inc.

Author information

Author notes

    • Jonathan G Seidman
    •  & Christine E Seidman

    These authors contributed equally to this study.


  1. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Steven C Greenway
    • , Jennifer C Lin
    • , Steven R DePalma
    • , Samuel J Israel
    • , Joshua M Korn
    • , Steven A McCarroll
    • , Joshua M Gorham
    • , David M Altshuler
    • , Maria de Lourdes Quintanilla-Dieck
    • , Maria Alexandra Artunduaga
    • , Jonathan G Seidman
    •  & Christine E Seidman
  2. Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo Medical School, São Paulo, Brazil.

    • Alexandre C Pereira
    •  & Sonia M Mesquita
  3. Department of Cardiology, Children's Hospital, Boston, Massachusetts, USA.

    • Emel Ergul
    • , Jessie H Conta
    •  & Roger E Breitbart
  4. The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Joshua M Korn
    • , Steven A McCarroll
    • , Stacey Gabriel
    • , David M Altshuler
    • , Robert M Plenge
    • , Philip L De Jager
    •  & David A Hafler
  5. Department of Otology and Laryngology, Massachusetts Eye & Ear Infirmary, Boston, Massachusetts, USA.

    • Maria de Lourdes Quintanilla-Dieck
    • , Maria Alexandra Artunduaga
    •  & Roland D Eavey
  6. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Robert M Plenge
    • , Nancy A Shadick
    •  & Michael E Weinblatt
  7. Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Philip L De Jager
    •  & David A Hafler
  8. Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Christine E Seidman


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S.C.G., A.C.P., R.E.B., J.G.S. and C.E.S. designed the experiments. S.C.G., J.C.L., S.J.I. and J.M.G. performed the experiments. S.C.G., S.R.D., J.M.K., S.A.M., S.G., D.M.A., J.G.S. and C.E.S. were involved in genotyping and data analysis. E.E., J.H.C., A.C.P., S.M.M., M.d.L.Q.-D., M.A.A., R.D.E., R.M.P., N.A.S., M.E.W., P.L.D.J., D.A.H. and R.E.B. recruited subjects and collected DNA. S.C.G., J.G.S. and C.E.S. wrote the paper with input from all authors.

Corresponding author

Correspondence to Christine E Seidman.

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