NSD1 mutations generate a genome-wide DNA methylation signature Journal Articles uri icon

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  • 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.


  • Choufani, S
  • Cytrynbaum, C
  • Chung, BHY
  • Turinsky, AL
  • Grafodatskaya, Daria
  • Chen, YA
  • Cohen, ASA
  • Dupuis, L
  • Butcher, DT
  • Siu, MT
  • Luk, HM
  • Lo, IFM
  • Lam, STS
  • Caluseriu, O
  • Stavropoulos, DJ
  • Reardon, W
  • Mendoza-Londono, R
  • Brudno, M
  • Gibson, WT
  • Chitayat, D
  • Weksberg, R

publication date

  • December 22, 2015