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

• Published in: American 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
• Language: English
• 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
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2020.03.008

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.