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

Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability
Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability
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 malignancies
1061-4036
385-388
Tatton-Brown, Katrina
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Seal, Sheila
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Ruark, Elise
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Harmer, Jenny
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Ramsay, Emma
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del Vecchio Duarte, Silvana
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Zachariou, Anna
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Hanks, Sandra
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O'Brien, Eleanor
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Aksglaede, Lise
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Baralle, Diana
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Dabir, Tabib
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Gener, Blanca
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Goudie, David
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Homfray, Tessa
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Kumar, Ajith
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Pilz, Daniela T.
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Selicorni, Angelo
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Temple, Karen I.
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Van Maldergem, Lionel
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Yachelevich, Naomi
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van Montfort, Robert
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Rahman, Nazneen
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Tatton-Brown, Katrina
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Seal, Sheila
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Ruark, Elise
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Harmer, Jenny
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Ramsay, Emma
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del Vecchio Duarte, Silvana
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Zachariou, Anna
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Hanks, Sandra
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O'Brien, Eleanor
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Aksglaede, Lise
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Baralle, Diana
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Dabir, Tabib
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Gener, Blanca
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Goudie, David
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Homfray, Tessa
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Kumar, Ajith
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Pilz, Daniela T.
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Selicorni, Angelo
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Temple, Karen I.
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Van Maldergem, Lionel
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Yachelevich, Naomi
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van Montfort, Robert
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Rahman, Nazneen
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Tatton-Brown, Katrina, Seal, Sheila, Ruark, Elise, Harmer, Jenny, Ramsay, Emma, del Vecchio Duarte, Silvana, Zachariou, Anna, Hanks, Sandra, O'Brien, Eleanor, Aksglaede, Lise, Baralle, Diana, Dabir, Tabib, Gener, Blanca, Goudie, David, Homfray, Tessa, Kumar, Ajith, Pilz, Daniela T., Selicorni, Angelo, Temple, Karen I., Van Maldergem, Lionel, Yachelevich, Naomi, van Montfort, Robert and Rahman, Nazneen (2014) Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nature Genetics, 46 (4), 385-388. (doi:10.1038/ng.2917). (PMID:24614070)

Record type: Article

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 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 malignancies

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Accepted/In Press date: 12 February 2014
e-pub ahead of print date: 9 March 2014
Published date: April 2014
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 363197
URI: http://eprints.soton.ac.uk/id/eprint/363197
ISSN: 1061-4036
PURE UUID: d71d6cc8-4bb6-4c75-a7fa-490e211e55a7
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833
ORCID for Karen I. Temple: ORCID iD orcid.org/0000-0002-6045-1781

Catalogue record

Date deposited: 24 Mar 2014 10:10
Last modified: 26 Nov 2021 02:53

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Contributors

Author: Katrina Tatton-Brown
Author: Sheila Seal
Author: Elise Ruark
Author: Jenny Harmer
Author: Emma Ramsay
Author: Silvana del Vecchio Duarte
Author: Anna Zachariou
Author: Sandra Hanks
Author: Eleanor O'Brien
Author: Lise Aksglaede
Author: Diana Baralle ORCID iD
Author: Tabib Dabir
Author: Blanca Gener
Author: David Goudie
Author: Tessa Homfray
Author: Ajith Kumar
Author: Daniela T. Pilz
Author: Angelo Selicorni
Author: Karen I. Temple ORCID iD
Author: Lionel Van Maldergem
Author: Naomi Yachelevich
Author: Robert van Montfort
Author: Nazneen Rahman

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