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...

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Published inAmerican journal of human genetics Vol. 106; no. 5; pp. 596 - 610
Main Authors 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, Weksberg, Rosanna
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 07.05.2020
Elsevier
Subjects
Abnormalities, Multiple - genetics
Adolescent
Adult
Child
Child, Preschool
Cohort Studies
Congenital Hypothyroidism - genetics
Craniofacial Abnormalities - genetics
DNA Methylation
DNA methylation signature
EED
Enhancer of Zeste Homolog 2 Protein - genetics
Female
Hand Deformities, Congenital - genetics
Humans
Infant
intellectual disability
Intellectual Disability - genetics
Male
Mosaicism
Mutation
Mutation, Missense - genetics
overgrowth syndromes
Polycomb Repressive Complex 2 - genetics
Reproducibility of Results
SUZ12
Young Adult
SUZ12
overgrowth syndromes
EED
intellectual disability
DNA methylation signature
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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.
AbstractList 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.
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.
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.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.
Author Weksberg, Rosanna
Choufani, Sanaa
Turinsky, Andrei L.
Garg, Kopal
Tatton-Brown, Katrina
Cytrynbaum, Cheryl
Tenconi, Romano
Cohen, Ana S.A.
Kerr, Bronwyn
White, Susan M.
Caluseriu, Oana
Iascone, Maria
Chitayat, David
Cushing, Tom
Scherer, Stephen W.
McConnell, Vivienne
Imagawa, Eri
Brzezinski, Jack
Gibson, William T.
Brudno, Michael
Cyrus, Sharri
Chung, Brian H.Y.
Okamoto, Nobuhiko
Goodman, Sarah
Clericuzio, Carol
Matsumoto, Naomichi
Temple, I. Karen
Vitriolo, Alessandro
Ming, Luk Ho
Machado, Jerry
Wang, Tianren
Bird, Lynne M.
Mendoza-Londono, Roberto
Splitt, Miranda
Testa, Guiseppe
Lynch, Sally Ann
Flinter, Frances
Chater-Diehl, Eric
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/32243864$$D View this record in MEDLINE/PubMed
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Fri Jul 11 08:11:36 EDT 2025
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Issue 5
Keywords SUZ12
overgrowth syndromes
EED
intellectual disability
DNA methylation signature
Language English
License This is an open access article under the CC BY-NC-ND license.
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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Snippet Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which...
Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2 , which...
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SubjectTerms Abnormalities, Multiple - genetics
Adolescent
Adult
Child
Child, Preschool
Cohort Studies
Congenital Hypothyroidism - genetics
Craniofacial Abnormalities - genetics
DNA Methylation
DNA methylation signature
EED
Enhancer of Zeste Homolog 2 Protein - genetics
Female
Hand Deformities, Congenital - genetics
Humans
Infant
intellectual disability
Intellectual Disability - genetics
Male
Mosaicism
Mutation
Mutation, Missense - genetics
overgrowth syndromes
Polycomb Repressive Complex 2 - genetics
Reproducibility of Results
SUZ12
Young Adult
Title DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes
URI https://dx.doi.org/10.1016/j.ajhg.2020.03.008
https://www.ncbi.nlm.nih.gov/pubmed/32243864
https://www.proquest.com/docview/2386287094
https://pubmed.ncbi.nlm.nih.gov/PMC7212265
Volume 106
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