DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes.
Abnormalities, Multiple
/ genetics
Adolescent
Adult
Child
Child, Preschool
Cohort Studies
Congenital Hypothyroidism
/ genetics
Craniofacial Abnormalities
/ genetics
DNA Methylation
Enhancer of Zeste Homolog 2 Protein
/ genetics
Female
Hand Deformities, Congenital
/ genetics
Humans
Infant
Intellectual Disability
/ genetics
Male
Mosaicism
Mutation
Mutation, Missense
/ genetics
Neoplasm Proteins
Polycomb Repressive Complex 2
/ genetics
Reproducibility of Results
Transcription Factors
Young Adult
DNA methylation signature
EED
SUZ12
intellectual disability
overgrowth syndromes
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
07 05 2020
07 05 2020
Historique:
received:
09
12
2019
accepted:
10
03
2020
pubmed:
4
4
2020
medline:
28
7
2020
entrez:
4
4
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32243864
pii: S0002-9297(20)30084-7
doi: 10.1016/j.ajhg.2020.03.008
pmc: PMC7212265
pii:
doi:
Substances chimiques
EED protein, human
0
Neoplasm Proteins
0
SUZ12 protein, human
0
Transcription Factors
0
EZH2 protein, human
EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
Polycomb Repressive Complex 2
EC 2.1.1.43
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
596-610Subventions
Organisme : CIHR
ID : IGH-155182
Pays : Canada
Organisme : CIHR
ID : MOP-126054
Pays : Canada
Organisme : CIHR
ID : PJT-148830
Pays : Canada
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
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