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 for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes / S. Choufani, W.T. Gibson, A.L. Turinsky, B.H.Y. Chung, T. Wang, K. Garg, A. Vitriolo, A.S.A. Cohen, S. Cyrus, S. Goodman, E. Chater-Diehl, J. Brzezinski, M. Brudno, L.H. Ming, S.M. White, S.A. Lynch, C. Clericuzio, I.K. Temple, F. Flinter, V. McConnell, T. Cushing, L.M. Bird, M. Splitt, B. Kerr, S.W. Scherer, J. Machado, E. Imagawa, N. Okamoto, N. Matsumoto, G. Testa, M. Iascone, R. Tenconi, O. Caluseriu, R. Mendoza-Londono, D. Chitayat, C. Cytrynbaum, K. Tatton-Brown, R. Weksberg. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - 106:5(2020), pp. 596-610. [10.1016/j.ajhg.2020.03.008]

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

Vitriolo A.;Testa G.;
2020

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.
DNA methylation signature; EED; intellectual disability; overgrowth syndromes; SUZ12; Abnormalities, Multiple; Adolescent; Adult; Child; Child, Preschool; Cohort Studies; Congenital Hypothyroidism; Craniofacial Abnormalities; Enhancer of Zeste Homolog 2 Protein; Female; Hand Deformities, Congenital; Humans; Infant; Intellectual Disability; Male; Mosaicism; Mutation, Missense; Polycomb Repressive Complex 2; Reproducibility of Results; Young Adult; DNA Methylation; Mutation
Settore BIO/11 - Biologia Molecolare
Settore BIO/18 - Genetica
Settore MED/03 - Genetica Medica
Settore BIO/13 - Biologia Applicata
Settore BIO/10 - Biochimica
Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica
Settore MED/39 - Neuropsichiatria Infantile
Functional role of Ezh2 mutations in Weaver Syndrome
Modeling Disease through Cell Reprogramming: a Translational Approach to the Pathogenesis of Syndromes Caused by Symmetrical Gene Dosage Imbalances
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/801637
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