TY - JOUR
T1 - DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes
AU - Choufani, Sanaa
AU - Gibson, William T.
AU - Turinsky, Andrei L.
AU - Chung, Brian H.Y.
AU - Wang, Tianren
AU - Garg, Kopal
AU - Vitriolo, Alessandro
AU - Cohen, Ana S.A.
AU - Cyrus, Sharri
AU - Goodman, Sarah
AU - Chater-Diehl, Eric
AU - Brzezinski, Jack
AU - Brudno, Michael
AU - Ming, Luk Ho
AU - White, Susan M.
AU - Lynch, Sally Ann
AU - Clericuzio, Carol
AU - Temple, I. Karen
AU - Flinter, Frances
AU - McConnell, Vivienne
AU - Cushing, Tom
AU - Bird, Lynne M.
AU - Splitt, Miranda
AU - Kerr, Bronwyn
AU - Scherer, Stephen W.
AU - Machado, Jerry
AU - Imagawa, Eri
AU - Okamoto, Nobuhiko
AU - Matsumoto, Naomichi
AU - Testa, Guiseppe
AU - Iascone, Maria
AU - Tenconi, Romano
AU - Caluseriu, Oana
AU - Mendoza-Londono, Roberto
AU - Chitayat, David
AU - Cytrynbaum, Cheryl
AU - Tatton-Brown, Katrina
AU - Weksberg, Rosanna
N1 - Funding Information:
We are grateful to all the families with childhood overgrowth conditions who participated in this research and to the many clinicians 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 (grant number GEP13105 to G.T.), the EPIGEN 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.
Funding Information:
We are grateful to all the families with childhood overgrowth conditions who participated in this research and to the many clinicians 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 (grant number GEP13105 to G.T.), the EPIGEN 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.
Publisher Copyright:
© 2020 The Author(s)
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/5/7
Y1 - 2020/5/7
N2 - 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.
AB - 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.
KW - DNA methylation signature
KW - EED
KW - intellectual disability
KW - overgrowth syndromes
KW - SUZ12
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U2 - 10.1016/j.ajhg.2020.03.008
DO - 10.1016/j.ajhg.2020.03.008
M3 - Article
C2 - 32243864
AN - SCOPUS:85084134777
VL - 106
SP - 596
EP - 610
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 5
ER -