TY - JOUR
T1 - Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability
AU - Tatton-Brown, Katrina
AU - Seal, Sheila
AU - Ruark, Elise
AU - Harmer, Jenny
AU - Ramsay, Emma
AU - del Vecchio Duarte, Silvana
AU - Zachariou, Anna
AU - Hanks, Sandra
AU - O'Brien, Eleanor
AU - Aksglaede, Lise
AU - Baralle, Diana
AU - Dabir, Tabib
AU - Gener, Blanca
AU - Goudie, David
AU - Homfray, Tessa
AU - Kumar, Ajith
AU - Pilz, Daniela T.
AU - Selicorni, Angelo
AU - Temple, I. Karen
AU - Van Maldergem, Lionel
AU - Yachelevich, Naomi
AU - Childhood Overgrowth Consortium
AU - van Montfort, Robert
AU - Rahman, Nazneen
PY - 2014/4
Y1 - 2014/4
N2 - 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.
AB - 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.
U2 - 10.1038/ng.2917
DO - 10.1038/ng.2917
M3 - Article
C2 - 24614070
SN - 1061-4036
VL - 46
SP - 385
EP - 388
JO - Nature Genetics
JF - Nature Genetics
IS - 4
ER -