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 dysmorphism. 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 leukemia. Thus, DNMT3A joins an emerging group of epigenetic DNA- and histone-modifying genes associated with both developmental growth disorders and hematological malignancies.
journal_name
Nat Genetjournal_title
Nature geneticsauthors
Tatton-Brown K,Seal S,Ruark E,Harmer J,Ramsay E,Del Vecchio Duarte S,Zachariou A,Hanks S,O'Brien E,Aksglaede L,Baralle D,Dabir T,Gener B,Goudie D,Homfray T,Kumar A,Pilz DT,Selicorni A,Temple IK,Van Maldergem L,Yacdoi
10.1038/ng.2917subject
Has Abstractpub_date
2014-04-01 00:00:00pages
385-8issue
4eissn
1061-4036issn
1546-1718pii
ng.2917journal_volume
46pub_type
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