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

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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)596-610
Number of pages15
JournalAmerican Journal of Human Genetics
Issue number5
Publication statusPublished - May 7 2020


  • DNA methylation signature
  • EED
  • intellectual disability
  • overgrowth syndromes
  • SUZ12

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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