Journal article

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

Sanaa Choufani, William T Gibson, Andrei L Turinsky, Brian HY Chung, Tianren Wang, Kopal Garg, Alessandro Vitriolo, Ana SA Cohen, Sharri Cyrus, Sarah Goodman, Eric Chater-Diehl, Jack Brzezinski, Michael Brudno, Luk Ho Ming, Susan M White, Sally Ann Lynch, Carol Clericuzio, I Karen Temple, Frances Flinter, Vivienne McConnell Show all

The American Journal of Human Genetics | CELL PRESS | Published : 2020


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 oth..

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Awarded by Canadian Institutes of Health Research (CIHR)

Awarded by CIHR Project Grant

Awarded by Telethon Foundation

Awarded by European Research Council

Funding Acknowledgements

We are grateful to all the families with childhood overgrowth conditionswhoparticipated in this research and to themanyclinicians who recruited them into the study. We also acknowledge the technical assistance of Youliang Lou and Chunhua Zhao. This work was supported by Canadian Institutes of Health Research (CIHR) grants to R.W. (IGH-155182 and MOP-126054), by CIHR Project Grant PJT-148830 to W.T.G., and by a BCCHR intramural IGAP salary award to W.T.G. Bioinformatic analyses were supported in part by the Canadian Centre for Computational Genomics (C3G), part of the Genome Technology Platform (GTP), funded by Genome Canada through Genome Quebec and Ontario Genomics (A.L.T., M.B.), Genome Canada through Ontario Genomics (A.L.T., S. Choufani, M.B., and R.W.), and the Ontario Brain Institute (OBI). OBI is an independent non-profit corporation, funded partially by the Ontario government. Protein Modeling was supported by Telethon Foundation (grantnumberGEP13105 to G.T.), the EPI GEN Flagship Project of the Italian National Research Council (to G.T.), the European Research Council (grant number 616441-DISEASEAVATARS to G.T.), and Ricerca Corrente granted by the Italian Ministry of Health (to G.T.). The opinions, results, and conclusions are those of the authors, and no endorsement by the Ontario Brain Institute is intended or should be inferred.