Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Anatomy and pathophysiology of tetralogy of Fallot.
Figure 2: CNVs associated with TOF.

Similar content being viewed by others

References

  1. Ferencz, C. et al. Congenital heart disease: prevalence at livebirth. The Baltimore-Washington Infant Study. Am. J. Epidemiol. 121, 31–36 (1985).

    Article  CAS  Google Scholar 

  2. Schott, J.J. et al. Congenital heart disease caused by mutations in the transcription factor NKX2–5. Science 281, 108–111 (1998).

    Article  CAS  Google Scholar 

  3. Basson, C.T. et al. Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome. Nat. Genet. 15, 30–35 (1997).

    Article  CAS  Google Scholar 

  4. Eldadah, Z.A. et al. Familial tetralogy of Fallot caused by mutation in the jagged1 gene. Hum. Mol. Genet. 10, 163–169 (2001).

    Article  CAS  Google Scholar 

  5. Tomita-Mitchell, A., Maslen, C.L., Morris, C.D., Garg, V. & Goldmuntz, E. GATA4 sequence variants in patients with congenital heart disease. J. Med. Genet. 44, 779–783 (2007).

    Article  CAS  Google Scholar 

  6. McDaniell, R. et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am. J. Hum. Genet. 79, 169–173 (2006).

    Article  CAS  Google Scholar 

  7. Garg, V. et al. Mutations in NOTCH1 cause aortic valve disease. Nature 437, 270–274 (2005).

    Article  CAS  Google Scholar 

  8. Goldmuntz, E. et al. Frequency of 22q11 deletions in patients with conotruncal defects. J. Am. Coll. Cardiol. 32, 492–498 (1998).

    Article  CAS  Google Scholar 

  9. Yagi, H. et al. Role of TBX1 in human del22q11.2 syndrome. Lancet 362, 1366–1373 (2003).

    Article  CAS  Google Scholar 

  10. Thienpont, B. et al. Submicroscopic chromosomal imbalances detected by array-CGH are a frequent cause of congenital heart defects in selected patients. Eur. Heart J. 28, 2778–2784 (2007).

    Article  CAS  Google Scholar 

  11. Richards, A.A. et al. Cryptic chromosomal abnormalities identified in children with congenital heart disease. Pediatr. Res. 64, 358–363 (2008).

    Article  Google Scholar 

  12. Loffredo, C.A. Epidemiology of cardiovascular malformations: prevalence and risk factors. Am. J. Med. Genet. 97, 319–325 (2000).

    Article  CAS  Google Scholar 

  13. Korn, J.M. et al. Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat. Genet. 40, 1253–1260 (2008).

    Article  CAS  Google Scholar 

  14. McCarroll, S.A. et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat. Genet. 40, 1166–1174 (2008).

    Article  CAS  Google Scholar 

  15. Sato, M. et al. The validity of a rheumatoid arthritis medical records-based index of severity compared with the DAS28. Arthritis Res. Ther. 8, R57 (2006).

    Article  Google Scholar 

  16. Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 444–454 (2006).

    Article  CAS  Google Scholar 

  17. Xu, B. et al. Strong association of de novo copy number mutations with sporadic schizophrenia. Nat. Genet. 40, 880–885 (2008).

    Article  CAS  Google Scholar 

  18. Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008).

    Article  CAS  Google Scholar 

  19. Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007).

    Article  CAS  Google Scholar 

  20. Christiansen, J. et al. Chromosome 1q21.1 contiguous gene deletion is associated with congenital heart disease. Circ. Res. 94, 1429–1435 (2004).

    Article  CAS  Google Scholar 

  21. de Vries, B.B. et al. Diagnostic genome profiling in mental retardation. Am. J. Hum. Genet. 77, 606–616 (2005).

    Article  CAS  Google Scholar 

  22. Brunetti-Pierri, N. et al. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat. Genet. 40, 1466–1471 (2008).

    Article  CAS  Google Scholar 

  23. Mefford, H.C. et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N. Engl. J. Med. 359, 1685–1699 (2008).

    Article  CAS  Google Scholar 

  24. International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237–241 (2008).

  25. Walsh, T. et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539–543 (2008).

    Article  CAS  Google Scholar 

  26. Sharp, A.J. et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat. Genet. 38, 1038–1042 (2006).

    Article  CAS  Google Scholar 

  27. Razzaque, M.A. et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat. Genet. 39, 1013–1017 (2007).

    Article  CAS  Google Scholar 

  28. Pandit, B. et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat. Genet. 39, 1007–1012 (2007).

    Article  CAS  Google Scholar 

  29. Bassett, A.S. et al. Clinical features of 78 adults with 22q11 deletion syndrome. Am. J. Med. Genet. A. 138, 307–313 (2005).

    Article  Google Scholar 

  30. McDonald-McGinn, D.M. et al. Phenotype of the 22q11.2 deletion in individuals identified through an affected relative: cast a wide FISHing net!. Genet. Med. 3, 23–29 (2001).

    Article  CAS  Google Scholar 

  31. Niessen, K. & Karsan, A. Notch signaling in cardiac development. Circ. Res. 102, 1169–1181 (2008).

    Article  CAS  Google Scholar 

  32. Krantz, I.D. et al. Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families. Am. J. Hum. Genet. 62, 1361–1369 (1998).

    Article  CAS  Google Scholar 

  33. Schubbert, S. et al. Germline KRAS mutations cause Noonan syndrome. Nat. Genet. 38, 331–336 (2006).

    Article  CAS  Google Scholar 

  34. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  35. Stern, R.F. et al. Multiplex ligation-dependent probe amplification using a completely synthetic probe set. Biotechniques 37, 399–405 (2004).

    Article  CAS  Google Scholar 

  36. Schouten, J.P. et al. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 30, e57 (2002).

    Article  Google Scholar 

  37. Yau, S.C., Bobrow, M., Mathew, C.G. & Abbs, S.J. Accurate diagnosis of carriers of deletions and duplications in Duchenne/Becker muscular dystrophy by fluorescent dosage analysis. J. Med. Genet. 33, 550–558 (1996).

    Article  CAS  Google Scholar 

  38. Kim, J.B. et al. Polony multiplex analysis of gene expression (PMAGE) in mouse hypertrophic cardiomyopathy. Science 316, 1481–1484 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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

Authors and Affiliations

Authors

Contributions

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.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Supplementary Tables 1–3 (PDF 2123 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Greenway, S., Pereira, A., Lin, J. et al. De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nat Genet 41, 931–935 (2009). https://doi.org/10.1038/ng.415

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.415

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing