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

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.

Figure 1

DNMT3A structure and mutations. Schematic representation of the protein structure of DNMT3A with (a) de novo mutations identified in overgrowth cases placed above the protein and (b) nonsynonymous variants identified in controls placed below the protein.

Figure 2

Characteristic facial appearance DNMT3A overgrowth syndrome. The mutation, growth parameters and other clinical features are given in Table 1 under the appropriate COG ID: (a) COG1288; (b) COG1670; (c) COG0422; (d) COG1695; (e) COG1688; (f) COG0109; (g) COG0553; (h) COG1512. Specific consent to publish facial photographs was obtained for all individuals.

Figure 3

Mutations mapped onto a structural model of the DNMT3A-DNMT3L complex. Two orientations of a model of the DNMT3A monomer generated by superposition of structures of the DNMT3A ADD domain (cyan), the DNMT3A MTase domain (light orange) and full-length DNMTL (green) show mutations in the MTase domain in purple and mutations in the ADD domain in pink. The histone peptide bound to the ADD domain is shown in orange and the position of the DNA is inferred by superposition of the structurally homologous bacterial cytosine methyltransferase HhaI-DNA complex. The model shows that the mutations in the MTase domain appear to be located at the interaction interface with its ADD domain and at the interface with DNMT3L. Mutations in the ADD domain are close to the histone-binding region.