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

TitleDNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes
Authors
Issue Date2020
PublisherCell Press. The Journal's web site is located at http://www.cell.com/ajhg/home
Citation
The American Journal of Human Genetics, 2020, Epub 2020-04-02, v. 106, p. 1-15 How to Cite?
AbstractWeaver 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 sequencevariants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.
Persistent Identifierhttp://hdl.handle.net/10722/281988
ISSN
2019 Impact Factor: 10.502
2015 SCImago Journal Rankings: 8.769

 

DC FieldValueLanguage
dc.contributor.authorChoufani, S-
dc.contributor.authorGibson, WT-
dc.contributor.authorTurinsky, AL-
dc.contributor.authorChung, BHY-
dc.contributor.authorWang, T-
dc.contributor.authorGarg, K-
dc.contributor.authorVitriolo, A-
dc.contributor.authorCohen, ASA-
dc.contributor.authorCyrus, S-
dc.contributor.authorGoodman, S-
dc.contributor.authorChater-Diehl, E-
dc.contributor.authorBrzezinski, J-
dc.contributor.authorBrudno, M-
dc.contributor.authorLuk, HM-
dc.contributor.authorWhite, SM-
dc.contributor.authorLynch, SA-
dc.contributor.authorClericuzio, C-
dc.contributor.authorTemple, IK-
dc.contributor.authorFlinter, F-
dc.contributor.authorMdConnell, V-
dc.contributor.authorCushing, T-
dc.contributor.authorBird, LM-
dc.contributor.authorSplitt, M-
dc.contributor.authorKerr, B-
dc.contributor.authorScherer, SW-
dc.contributor.authorMachado, J-
dc.contributor.authorImagawa, E-
dc.contributor.authorOkamoto, N-
dc.contributor.authorMatsumoto, N-
dc.contributor.authorTesta, G-
dc.contributor.authorIascone, M-
dc.contributor.authorTenconi, R-
dc.contributor.authorCaluseriu, O-
dc.contributor.authorMendoza-Londono, R-
dc.contributor.authorChitayat, D-
dc.contributor.authorCytrynabum, C-
dc.contributor.authorTatton-Brown, K-
dc.contributor.authorWeksberg, R-
dc.date.accessioned2020-04-19T03:33:48Z-
dc.date.available2020-04-19T03:33:48Z-
dc.date.issued2020-
dc.identifier.citationThe American Journal of Human Genetics, 2020, Epub 2020-04-02, v. 106, p. 1-15-
dc.identifier.issn0002-9297-
dc.identifier.urihttp://hdl.handle.net/10722/281988-
dc.description.abstractWeaver 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 sequencevariants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.-
dc.languageeng-
dc.publisherCell Press. The Journal's web site is located at http://www.cell.com/ajhg/home-
dc.relation.ispartofThe American Journal of Human Genetics-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleDNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes-
dc.typeArticle-
dc.identifier.emailChung, BHY: bhychung@hku.hk-
dc.identifier.emailLuk, HM: lukhm@hku.hk-
dc.identifier.authorityChung, BHY=rp00473-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1016/j.ajhg.2020.03.008-
dc.identifier.scopuseid_2-s2.0-85084134777-
dc.identifier.hkuros309762-
dc.identifier.volumeEpub 2020-04-02, v. 106-
dc.identifier.spage1-
dc.identifier.epage15-
dc.publisher.placeUnited States-

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