DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes

Abstract

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2 , which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12 , which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2 , EED , and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.

Novel DNMT3A Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma

“…Herein we have demonstrated that blood DNA from a patient with microcephalic dwarfism shows a similar profile to the observed for PGL patients, suggesting that a comparable activation of DNMT3A is occurring in both phenotypes. Moreover, overall alterations of DNA methylation have been also observed in blood cells from TET2 (hypermethylation) or EZH2 (hypomethylation) germline pathogenic loss-of-function variant carriers [28,29]. Thus, the methylated signature found in saliva DNA from the PGL patient described herein further supports the activating role of the new germline alteration found within the PWWP domain of DNMT3A.…”

Epigenome-wide meta-analysis of DNA methylation differences in prefrontal cortex implicates the immune processes in Alzheimer’s disease

“…Although the targeting of PRC2 to methylated CpGs has also been shown in vitro 59 , PRC2 typically binds to unmethylated CpG islands 60 at the promoters of inactive developmental genes. Dysfunction of PRC2 is associated with alterations of DNA methylation of CpGs in promoters of developmental genes 61 . Conversely, it has also been shown that loss of DNA methylation results in enhanced H3K27me3, suggesting that PRC2 can serve as a back-up repressive complex for newly hypomethylated CpGs.…”

Detection of a DNA Methylation Signature for the Intellectual Developmental Disorder, X-Linked, Syndromic, Armfield Type

“…One limitation of genome-wide methylation analysis for Mendelian neurodevelopmental disorders is that these syndromes are generally very rare. We expect that by increasing the number of samples and expanding the range and type of variants we may uncover further sub-stratification of the DNA methylation profile of FAM50A , as we have previously observed for conditions including Weaver syndrome (WVS) and Coffin–Siris syndrome (CSS) [ 8 , 17 , 40 ].…”