Authors
Choufani, SCytrynbaum, 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
Luk, H M
Lo, I F M
Lam, S T S
Caluseriu, O
Stavropoulos, D J
Reardon, W
Mendoza-Londono, R
Brudno, M
Gibson, W T
Chitayat, D
Weksberg, R
Issue Date
2015-12-22Keywords
INTELLECTUAL DISABILITIESGENETICS
MeSH
DNA MethylationGene Expression Regulation
Genome, Human
Humans
Intracellular Signaling Peptides and Proteins
Mutation
Nuclear Proteins
Sotos Syndrome
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NSD1 mutations generate a genome-wide DNA methylation signature. 2015, 6:10207 Nat CommunPublisher
Nature Publishing GroupJournal
Nature communicationsDOI
10.1038/ncomms10207PubMed ID
26690673Abstract
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.Item Type
ArticleLanguage
enISSN
2041-1723ae974a485f413a2113503eed53cd6c53
10.1038/ncomms10207
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