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

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    Author
    Choufani, S; Gibson, WT; Turinsky, AL; Chung, BHY; Wang, T; Garg, K; Vitriolo, A; Cohen, ASA; Cyrus, S; Goodman, S; ...
    Date
    2020-05-07
    Source Title
    American Journal of Human Genetics
    Publisher
    CELL PRESS
    University of Melbourne Author/s
    White, Susan
    Affiliation
    Paediatrics (RCH)
    Metadata
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    Document Type
    Journal Article
    Citations
    Choufani, S., Gibson, W. T., Turinsky, A. L., Chung, B. H. Y., Wang, T., Garg, K., Vitriolo, A., Cohen, A. S. A., Cyrus, S., Goodman, S., Chater-Diehl, E., Brzezinski, J., Brudno, M., Ming, L. H., White, S. M., Lynch, S. A., Clericuzio, C., Temple, I. K., Flinter, F. ,... Weksberg, R. (2020). DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes. AMERICAN JOURNAL OF HUMAN GENETICS, 106 (5), pp.596-610. https://doi.org/10.1016/j.ajhg.2020.03.008.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/251459
    DOI
    10.1016/j.ajhg.2020.03.008
    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.

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