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Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability

A Corrigendum to this article was published on 28 May 2014

This article has been updated


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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Figure 1: DNMT3A structure and summary of variants.
Figure 2: Characteristic facial appearance in DNMT3A overgrowth syndrome.
Figure 3: Protein alterations mapped onto a structural model of the DNMT3A-DNMT3L complex.

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  • 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.


  1. 1

    Tatton-Brown, K. & Weksberg, R. Molecular mechanisms of childhood overgrowth. Am. J. Med. Genet. C. Semin. Med. Genet. 163C, 71–75 (2013).

    Article  Google Scholar 

  2. 2

    Jurkowska, R.Z., Jurkowski, T.P. & Jeltsch, A. Structure and function of mammalian DNA methyltransferases. ChemBioChem 12, 206–222 (2011).

    CAS  Article  Google Scholar 

  3. 3

    Ley, T.J. et al. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363, 2424–2433 (2010).

    CAS  Article  Google Scholar 

  4. 4

    Yan, X.J. et al. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat. Genet. 43, 309–315 (2011).

    CAS  Article  Google Scholar 

  5. 5

    Tatton-Brown, K. & Rahman, N. The NSD1 and EZH2 overgrowth genes, similarities and differences. Am. J. Med. Genet. C. Semin. Med. Genet. 163C, 86–91 (2013).

    Article  Google Scholar 

  6. 6

    Durand, C. & Rappold, G.A. Height matters—from monogenic disorders to normal variation. Nat. Rev. Endocrinol. 9, 171–177 (2013).

    CAS  Article  Google Scholar 

  7. 7

    Rush, M. et al. Targeting of EZH2 to a defined genomic site is sufficient for recruitment of Dnmt3a but not de novo DNA methylation. Epigenetics 4, 404–414 (2009).

    CAS  Article  Google Scholar 

  8. 8

    Tatton-Brown, K. et al. Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height. Oncotarget 2, 1127–1133 (2011).

    Article  Google Scholar 

  9. 9

    Freeman, J.V et al. Cross sectional stature and weight reference curves for the UK, 1990. Arch. Dis. Child. 73, 17–24 (1995).

    CAS  Article  Google Scholar 

  10. 10

    Okano, M., Bell, D.W., Haber, D.A. & Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999).

    CAS  Article  Google Scholar 

  11. 11

    Smallwood, S.A. & Kelsey, G. De novo DNA methylation: a germ cell perspective. Trends Genet. 28, 33–42 (2012).

    CAS  Article  Google Scholar 

  12. 12

    Kaneda, M. et al. Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature 429, 900–903 (2004).

    CAS  Article  Google Scholar 

  13. 13

    Chedin, F., Lieber, M.R. & Hsieh, C.L. The DNA methyltransferase–like protein DNMT3L stimulates de novo methylation by Dnmt3a. Proc. Natl. Acad. Sci. USA 99, 16916–16921 (2002).

    CAS  Article  Google Scholar 

  14. 14

    Hata, K., Okano, M., Lei, H. & Li, E. Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development 129, 1983–1993 (2002).

    CAS  Google Scholar 

  15. 15

    Suetake, I., Shinozaki, F., Miyagawa, J., Takeshima, H. & Tajima, S. DNMT3L stimulates the DNA methylation activity of Dnmt3a and Dnmt3b through a direct interaction. J. Biol. Chem. 279, 27816–27823 (2004).

    CAS  Article  Google Scholar 

  16. 16

    Abdel-Wahab, O. & Levine, R.L. Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia. Blood 121, 3563–3572 (2013).

    CAS  Article  Google Scholar 

  17. 17

    Marcucci, G. et al. Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. J. Clin. Oncol. 30, 742–750 (2012).

    Article  Google Scholar 

  18. 18

    Nikoloski, G., van der Reijden, B.A. & Jansen, J.H. Mutations in epigenetic regulators in myelodysplastic syndromes. Int. J. Hematol. 95, 8–16 (2012).

    Article  Google Scholar 

  19. 19

    Kim, S.J. et al. A DNMT3A mutation common in AML exhibits dominant-negative effects in murine ES cells. Blood 122, 4086–4089 (2013).

    CAS  Article  Google Scholar 

  20. 20

    Otani, J. et al. Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain. EMBO Rep. 10, 1235–1241 (2009).

    CAS  Article  Google Scholar 

  21. 21

    Tatton-Brown, K. et al. Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. Am. J. Hum. Genet. 77, 193–204 (2005).

    CAS  Article  Google Scholar 

  22. 22

    Lund, K., Adams, P.D. & Copland, M. EZH2 in normal and malignant hematopoiesis. Leukemia 28, 44–49 (2014).

    CAS  Article  Google Scholar 

  23. 23

    Cerveira, N. et al. Frequency of NUP98-NSD1 fusion transcript in childhood acute myeloid leukaemia. Leukemia 17, 2244–2247 (2003).

    CAS  Article  Google Scholar 

  24. 24

    Cao, R. & Zhang, Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr. Opin. Genet. Dev. 14, 155–164 (2004).

    CAS  Article  Google Scholar 

  25. 25

    Morishita, M. & di Luccio, E. Structural insights into the regulation and the recognition of histone marks by the SET domain of NSD1. Biochem. Biophys. Res. Commun. 412, 214–219 (2011).

    CAS  Article  Google Scholar 

  26. 26

    Hoischen, A. et al. De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome. Nat. Genet. 43, 729–731 (2011).

    CAS  Article  Google Scholar 

  27. 27

    Lunter, G. & Goodson, M. Stampy: a statistical algorithm for sensitive and fast mapping of Illumina sequence reads. Genome Res. 21, 936–939 (2011).

    CAS  Article  Google Scholar 

  28. 28

    Rimmer, A., Mathieson, I., Lunter, G. & McVean, G. Platypus: an integrated variant caller,

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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





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.

Corresponding authors

Correspondence to Katrina Tatton-Brown or Nazneen Rahman.

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The authors declare no competing financial interests.

Additional information

A full list of members appears in the Supplementary Note.

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Supplementary Tables 1 and 2, Supplementary Figure 1 and Supplementary Note (PDF 429 kb)

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Tatton-Brown, K., Seal, S., Ruark, E. et al. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat Genet 46, 385–388 (2014).

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