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

Choufani, S; Gibson, WT; Turinsky, AL; Chung, BHY; Wang, T; Garg, K; Vitriolo, A; Cohen, ASA; Cyrus, S; Goodman, S; et al. Choufani, S; Gibson, WT; Turinsky, AL; Chung, BHY; Wang, T; Garg, K; Vitriolo, A; Cohen, ASA; Cyrus, S; Goodman, S; Chater-Diehl, E; Brzezinski, J; Brudno, M; Ming, LH; White, SM; Lynch, SA; Clericuzio, C; Temple, IK; Flinter, F; McConnell, V; Cushing, T; Bird, LM; Splitt, M; Kerr, B; Scherer, SW; Machado, J; Imagawa, E; Okamoto, N; Matsumoto, N; Testa, G; Iascone, M; Tenconi, R; Caluseriu, O; Mendoza-Londono, R; Chitayat, D; Cytrynbaum, C; Tatton-Brown, K; Weksberg, R (2020) DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes. Am J Hum Genet, 106 (5). pp. 596-610. ISSN 1537-6605 https://doi.org/10.1016/j.ajhg.2020.03.008
SGUL Authors: Tatton-Brown, Katrina Louise

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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.

Item Type: Article
Additional Information: © 2020 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: DNA methylation signature, EED, SUZ12, intellectual disability, overgrowth syndromes, Genetics & Heredity, 06 Biological Sciences, 11 Medical and Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Journal or Publication Title: Am J Hum Genet
ISSN: 1537-6605
Language: eng
Dates:
DateEvent
7 May 2020Published
2 April 2020Published Online
10 March 2020Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Projects:
Project IDFunderFunder ID
IGH-155182Canadian Institutes of Health Researchhttp://dx.doi.org/10.13039/501100000024
MOP-126054Canadian Institutes of Health Researchhttp://dx.doi.org/10.13039/501100000024
PJT-148830Canadian Institutes of Health Researchhttp://dx.doi.org/10.13039/501100000024
GEP13105Fondazione Telethonhttp://dx.doi.org/10.13039/501100002426
616441-DISEASEAVATARSEuropean Research Councilhttp://dx.doi.org/10.13039/501100000781
PubMed ID: 32243864
Web of Science ID: WOS:000531096100002
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/112038
Publisher's version: https://doi.org/10.1016/j.ajhg.2020.03.008

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