Sanaa Choufani, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
William T. Gibson, British Columbia Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada
Andrei L. Turinsky, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Centre for Computational Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Brian H Y Chung, Pediatrics and Adolescent Medicine, Queen Mary Hospital and Hong Kong Children's Hospital, The University of Hong Kong, 999077 Hong Kong
Tianren Wang, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Kopal Garg, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Alessandro Vitriolo, Department of Oncology and Hemato-oncology, University of Milan, Milan 20122, Italy; Laboratory of Stem Cell Epigenetics, IEO, European Institute of Oncology, IRCCS, Milan 20139, Italy
Ana S A Cohen, British Columbia Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Sharri Cyrus, British Columbia Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada
Sarah Goodman, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Eric Chater-Diehl, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Jack Brzezinski, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Haematology and Oncology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada
Michael Brudno, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Centre for Computational Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5S 3H5, Canada
Luk Ho Ming, Clinical Genetic Service, Department of Health, 999077 Hong Kong
Susan M. White, Victorian Clinical Genetics Service, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia
Sally Ann Lynch, Department of Clinical Genetics, Temple Street Children's University Hospital, Dublin, D01 XD99, Ireland
Carol Clericuzio, Pediatric Genetics, University of New Mexico, Albuquerque, NM 87131, USA
I Karen Temple, Faculty of Medicine, University of Southampton and the Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
Frances Flinter, Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London SE1 9RT, UK
Vivienne McConnell, Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast BT9 7AB, UK
Tom Cushing, Pediatric Genetics, University of New Mexico, Albuquerque, NM 87131, USA
Lynne M. Bird, Department of Pediatrics, University of California, San Diego, San Diego, CA 92093, USA; Division of Genetics, Rady Children's Hospital of San Diego, San Diego, CA 92123, USA
Miranda Splitt, Northern Genetics Service, Institute of Genetics Medicine, Newcastle upon Tyne NE1 3BZ, UK
Bronwyn Kerr, Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester M13 9PL, UK; Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK
Stephen W. Scherer, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8 Canada; McLaughlin Centre, University of Toronto, Toronto, ON M5S 1A1, Canada
Jerry Machado, PreventionGenetics, Marshfield, WI 54449, USA
Eri Imagawa, Department of Human Genetics, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama 236-0004, Japan
Nobuhiko Okamoto, Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka 594-1101, Japan
Naomichi Matsumoto, Department of Human Genetics, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama 236-0004, Japan
Guiseppe Testa, Department of Oncology and Hemato-oncology, University of Milan, Milan 20122, Italy; Laboratory of Stem Cell Epigenetics, IEO, European Institute of Oncology, IRCCS, Milan 20139, Italy; Human Technopole, Center for Neurogenomics, Via Cristina Belgioioso 171, Milan 20157, Italy
Maria Iascone, Laboratorio di Genetica Medica, ASST Papa Giovanni XXIII, Piazza OMS 1, 24127 Bergamo, Italy
Romano Tenconi, Dipartimento Pediatria, University of Padova, Via Giustiani 3, 35128 Padova, Italy
Oana Caluseriu, Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, Canada; The Stollery Pediatric Hospital, Edmonton, AB T6G 2H7, Canada
Roberto Mendoza-Londono, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5S 1A1, Canada
David Chitayat, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5S 1A1, Canada; Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
Cheryl Cytrynbaum, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada
Katrina Tatton-Brown, St George's University Hospitals NHS Foundation Trust, London SW17 0QT, UK; St George's, University of London, London SW17 0RE, UK; Section of Cancer Genetics, Institute of Cancer Research, Surrey SM2 5NG, UK
Rosanna Weksberg, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5S 1A1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada

Document Type

Article

Publication Date

5-7-2020

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.

Publication Title

American journal of human genetics

ISSN

1537-6605

Volume

106

Issue

5

First Page

596

Last Page

610

DOI

10.1016/j.ajhg.2020.03.008

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