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DNA methylation signature for EZH2 functionally classifies sequence variants in three PRC2 complex genes

DNA methylation signature for EZH2 functionally classifies sequence variants in three PRC2 complex genes
DNA methylation signature for EZH2 functionally classifies sequence variants in three PRC2 complex genes
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.
DNA methylation signature, EED, SUZ12, intellectual disability, overgrowth syndromes
0002-9297
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Choufani, Sanaa, Gibson, William T., Turinsky, Andrei L., Chung, Brian H.Y., Wang, Tianren, Garg, Kopal, Vitriolo, Alessandro, Cohen, Ana S.A., Cyrus, Sharri, Goodman, Sarah, Chater-Diehl, Eric, Brzezinski, Jack, Brudno, Michael, Ming, Luk Ho, White, Susan M., Lynch, Sally Ann, Clericuzio, Carol, Temple, I. Karen, Flinter, Frances, Mcconnell, Vivienne, Cushing, Tom, Bird, Lynne M., Splitt, Miranda, Kerr, Bronwyn, Scherer, Stephen W., Machado, Jerry, Imagawa, Eri, Okamoto, Nobuhiko, Matsumoto, Naomichi, Testa, Guiseppe, Iascone, Maria, Tenconi, Romano, Caluseriu, Oana, Mendoza-londono, Roberto, Chitayat, David, Cytrynbaum, Cheryl, Tatton-Brown, Katrina and Weksberg, Rosanna (2020) DNA methylation signature for EZH2 functionally classifies sequence variants in three PRC2 complex genes. The American Journal of Human Genetics, 106 (5), 596-610. (doi:10.1016/j.ajhg.2020.03.008).

Record type: Article

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.

Text
AJHG-D-19-00804_R3-1 - Accepted Manuscript
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More information

Accepted/In Press date: 10 March 2020
e-pub ahead of print date: 2 April 2020
Published date: 7 May 2020
Keywords: DNA methylation signature, EED, SUZ12, intellectual disability, overgrowth syndromes

Identifiers

Local EPrints ID: 443527
URI: http://eprints.soton.ac.uk/id/eprint/443527
ISSN: 0002-9297
PURE UUID: 295f04f6-7545-4d1b-ae92-ac3cefebe7ca
ORCID for I. Karen Temple: ORCID iD orcid.org/0000-0002-6045-1781

Catalogue record

Date deposited: 28 Aug 2020 16:30
Last modified: 26 Nov 2021 06:34

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Contributors

Author: Sanaa Choufani
Author: William T. Gibson
Author: Andrei L. Turinsky
Author: Brian H.Y. Chung
Author: Tianren Wang
Author: Kopal Garg
Author: Alessandro Vitriolo
Author: Ana S.A. Cohen
Author: Sharri Cyrus
Author: Sarah Goodman
Author: Eric Chater-Diehl
Author: Jack Brzezinski
Author: Michael Brudno
Author: Luk Ho Ming
Author: Susan M. White
Author: Sally Ann Lynch
Author: Carol Clericuzio
Author: I. Karen Temple ORCID iD
Author: Frances Flinter
Author: Vivienne Mcconnell
Author: Tom Cushing
Author: Lynne M. Bird
Author: Miranda Splitt
Author: Bronwyn Kerr
Author: Stephen W. Scherer
Author: Jerry Machado
Author: Eri Imagawa
Author: Nobuhiko Okamoto
Author: Naomichi Matsumoto
Author: Guiseppe Testa
Author: Maria Iascone
Author: Romano Tenconi
Author: Oana Caluseriu
Author: Roberto Mendoza-londono
Author: David Chitayat
Author: Cheryl Cytrynbaum
Author: Katrina Tatton-Brown
Author: Rosanna Weksberg

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