NSD1 mutations generate a genome-wide DNA methylation signature

Nat Commun. 2015 Dec 22;6:10207. doi: 10.1038/ncomms10207.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Methylation / genetics*
  • Gene Expression Regulation
  • Genome, Human*
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Sotos Syndrome / genetics*

Substances

  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • NSD1 protein, human