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NSD1 mutations generate a genome-wide DNA methylation signature.
Choufani, S Cytrynbaum, C Chung, B H Y Turinsky, A L Grafodatskaya, D Chen, Y A Cohen, A S A Dupuis, L Butcher, D T Siu, M T
Choufani, S
Cytrynbaum, C
Chung, B H Y
Turinsky, A L
Grafodatskaya, D
Chen, Y A
Cohen, A S A
Dupuis, L
Butcher, D T
Siu, M T
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Date
2015-12-22
Date Submitted
Keywords
INTELLECTUAL DISABILITIES
GENETICS
GENETICS
Other Subjects
Subject Mesh
DNA Methylation
Gene Expression Regulation
Genome, Human
Humans
Intracellular Signaling Peptides and Proteins
Mutation
Nuclear Proteins
Sotos Syndrome
Gene Expression Regulation
Genome, Human
Humans
Intracellular Signaling Peptides and Proteins
Mutation
Nuclear Proteins
Sotos Syndrome
Planned Date
Start Date
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Principal Investigators
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OA Article
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Abstract
Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1. As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1(+/-)-specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1(+/-) signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing.
Language
en
ISSN
2041-1723
eISSN
ISBN
DOI
10.1038/ncomms10207
PMID
26690673