• A Corrigendum to this article was published on 28 May 2014

This article has been updated

Abstract

Overgrowth disorders are a heterogeneous group of conditions characterized by increased growth parameters and other variable clinical features such as intellectual disability and facial dysmorphism1. To identify new causes of human overgrowth, we performed exome sequencing in ten proband-parent trios and detected two de novo DNMT3A mutations. We identified 11 additional de novo mutations by sequencing DNMT3A in a further 142 individuals with overgrowth. The mutations alter residues in functional DNMT3A domains, and protein modeling suggests that they interfere with domain-domain interactions and histone binding. Similar mutations were not present in 1,000 UK population controls (13/152 cases versus 0/1,000 controls; P < 0.0001). Mutation carriers had a distinctive facial appearance, intellectual disability and greater height. DNMT3A encodes a DNA methyltransferase essential for establishing methylation during embryogenesis and is commonly somatically mutated in acute myeloid leukemia2,3,4. Thus, DNMT3A joins an emerging group of epigenetic DNA- and histone-modifying genes associated with both developmental growth disorders and hematological malignancies5.

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Change history

  • 25 April 2014

    In the version of this article initially published, the protein alterations for three cases (COG1770, COG1670 and COG0141) were listed incorrectly in Table 1. The correct protein alterations for these three cases are p.Ile310Asn, p.Ser312fs and p.Gly532Ser, respectively. These errors have been corrected in the HTML and PDF versions of the article.

Accessions

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Acknowledgements

We thank the families for their participation in our research and the physicians and nurses who recruited them. Samples were collected through the Childhood Overgrowth Collaboration; a full list of collaborators is presented in the Supplementary Note. We are grateful to M. Warren-Perry, D. Dudakia and J. Bull for assistance in recruitment and to E. Moran (New York University Hospital for Joint Diseases) and A. Murray (University Hospital of Wales) for their clinical input for COG1770 and COG0109, respectively. We thank A. Strydom for assistance in preparing the manuscript. We are grateful to G. Lunter and M. Münz (Wellcome Trust Centre for Human Genetics, Oxford University) for their contributions to the development of the custom annotation tool SAVANT. We acknowledge use of services provided by the Institute of Cancer Research Genetics Core Facility, which is managed by S.H. and N.R. We acknowledge National Health Service (NHS) funding to the Royal Marsden/Institute of Cancer Research National Institute for Health Research (NIHR) Biomedical Research Centre. We also thank Mariani Foundation Milan for supporting the clinical activity of Genetica Clinica Pediatrica, Fondazione MBBM, AO San Gerardo Monza. This research was supported by the Wellcome Trust (100210/Z/12/Z) and by the Institute of Cancer Research, London.

Author information

Affiliations

  1. Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.

    • Katrina Tatton-Brown
    • , Sheila Seal
    • , Elise Ruark
    • , Emma Ramsay
    • , Silvana del Vecchio Duarte
    • , Anna Zachariou
    • , Sandra Hanks
    • , Eleanor O'Brien
    •  & Nazneen Rahman
  2. Cancer Genetics Unit, Royal Marsden Hospital, London, UK.

    • Katrina Tatton-Brown
    •  & Nazneen Rahman
  3. Medical Genetics, St George's University of London, London, UK.

    • Katrina Tatton-Brown
    •  & Tessa Homfray
  4. Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, Institute of Cancer Research, London, UK.

    • Jenny Harmer
    •  & Robert van Montfort
  5. Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark.

    • Lise Aksglaede
  6. Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.

    • Diana Baralle
    •  & I Karen Temple
  7. Northern Ireland Regional Genetics Centre, Clinical Genetics Service, Belfast City Hospital, Belfast, UK.

    • Tabib Dabir
  8. Servicio de Genética, BioCruces Health Research Institute, Hospital Universitario Cruces, Bizkaia, Spain.

    • Blanca Gener
  9. Department of Human Genetics, Ninewells Hospital and Medical School, Dundee, UK.

    • David Goudie
  10. North East Thames Regional Genetics Service, Great Ormond Street Hospital, London, UK.

    • Ajith Kumar
  11. Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.

    • Daniela T Pilz
  12. Ambulatorio di Genetica Clinica Pediatrica, Clinica Pediatrica dell'Università di Milano Bicocca, La Fondazione Monza e Brianza il Bambino e La Sua Mamma (MBBM), Azienda Ospedaliera (AO), San Gerado, Monza, Italy.

    • Angelo Selicorni
  13. Centre de Génétique Humaine, Université de Franche-Comté, Besançon, France.

    • Lionel Van Maldergem
  14. Clinical Genetics Services, New York University Hospitals Center, New York University, New York, New York, USA.

    • Naomi Yachelevich

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  1. Childhood Overgrowth Consortium

    A full list of members appears in the Supplementary Note.

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Contributions

S.S., E. Ramsay., S.d.V.D., S.H. and E.O. undertook the molecular analyses. E. Ruark undertook the bioinformatics analyses. A.Z. coordinated recruitment. L.A., D.B., T.D., B.G., D.G., T.H., A.K., D.T.P., A.S., I.K.T., L.V.M., N.Y. and K.T.-B. collected samples and undertook phenotyping. J.H. and R.v.M. undertook the protein modeling. N.R. and K.T.-B. designed and oversaw the project and wrote the manuscript with input from other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Katrina Tatton-Brown or Nazneen Rahman.

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Supplementary information

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    Supplementary Text and Figures

    Supplementary Tables 1 and 2, Supplementary Figure 1 and Supplementary Note

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DOI

https://doi.org/10.1038/ng.2917

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