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

Katrina Tatton-Brown (Lead / Corresponding author), Sheila Seal, Elise Ruark, Jenny Harmer, Emma Ramsay, Silvana del Vecchio Duarte, Anna Zachariou, Sandra Hanks, Eleanor O'Brien, Lise Aksglaede, Diana Baralle, Tabib Dabir, Blanca Gener, David Goudie, Tessa Homfray, Ajith Kumar, Daniela T. Pilz, Angelo Selicorni, I. Karen Temple, Lionel Van MaldergemNaomi Yachelevich, Childhood Overgrowth Consortium, Robert van Montfort, Nazneen Rahman (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    244 Citations (Scopus)


    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.
    Original languageEnglish
    Pages (from-to)385-388
    Number of pages4
    JournalNature Genetics
    Issue number4
    Publication statusPublished - Apr 2014


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