DNA methylation signature to diagnose certain growth syndromes

DNA methylation signature to diagnose certain growth syndromes

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, authors 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, researchers identify a genome-wide, highly significant NSD1+/−-specific signature that differentiates pathogenic NSD1mutations 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.