Chung, B H Y
Turinsky, A L
Chen, Y A
Cohen, A S A
Butcher, D T
Siu, M T
Luk, H M
Lo, I F M
Lam, S T S
Stavropoulos, D J
Gibson, W T
Gene Expression Regulation
Intracellular Signaling Peptides and Proteins
MetadataShow full item record
CitationNSD1 mutations generate a genome-wide DNA methylation signature. 2015, 6:10207 Nat Commun
PublisherNature Publishing Group
AbstractSotos 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.
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