Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 106, Issue 5, Pages 596-610Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2020.03.008
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Funding
- Canadian Institutes of Health Research (CIHR) [IGH-155182, MOP-126054]
- CIHR Project Grant [PJT-148830]
- BCCHR intramural IGAP salary award
- Canadian Centre for Computational Genomics (C3G)
- Genome Technology Platform (GTP) - Genome Canada through Genome Quebec and Ontario Genomics
- Genome Canada through Ontario Genomics
- Ontario Brain Institute (OBI)
- Ontario government
- Telethon Foundation [GEP13105]
- EPI GEN Flagship Project of the Italian National Research Council
- European Research Council [616441-DISEASEAVATARS]
- Italian Ministry of Health
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Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyl-transferase 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.
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