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 McConnell; Tom 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

doi:10.1016/j.ajhg.2020.03.008

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

Am J Hum Genet. 2020 May 7;106(5):596-610. doi: 10.1016/j.ajhg.2020.03.008. Epub 2020 Apr 2.

Authors

Sanaa Choufani¹, William T Gibson², Andrei L Turinsky³, Brian H Y Chung⁴, Tianren Wang¹, Kopal Garg¹, Alessandro Vitriolo⁵, Ana S A Cohen⁶, Sharri Cyrus², Sarah Goodman¹, Eric Chater-Diehl¹, Jack Brzezinski⁷, Michael Brudno⁸, Luk Ho Ming⁹, Susan M White¹⁰, Sally Ann Lynch¹¹, Carol Clericuzio¹², I Karen Temple¹³, Frances Flinter¹⁴, Vivienne McConnell¹⁵, Tom Cushing¹², Lynne M Bird¹⁶, Miranda Splitt¹⁷, Bronwyn Kerr¹⁸, Stephen W Scherer¹⁹, Jerry Machado²⁰, Eri Imagawa²¹, Nobuhiko Okamoto²², Naomichi Matsumoto²¹, Guiseppe Testa²³, Maria Iascone²⁴, Romano Tenconi²⁵, Oana Caluseriu²⁶, Roberto Mendoza-Londono²⁷, David Chitayat²⁸, Cheryl Cytrynbaum²⁹, Katrina Tatton-Brown³⁰, Rosanna Weksberg³¹

Affiliations

¹ Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
² 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.
³ 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.
⁴ Pediatrics and Adolescent Medicine, Queen Mary Hospital and Hong Kong Children's Hospital, The University of Hong Kong, 999077 Hong Kong.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ Clinical Genetic Service, Department of Health, 999077 Hong Kong.
¹⁰ Victorian Clinical Genetics Service, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
¹¹ Department of Clinical Genetics, Temple Street Children's University Hospital, Dublin, D01 XD99, Ireland.
¹² Pediatric Genetics, University of New Mexico, Albuquerque, NM 87131, USA.
¹³ Faculty of Medicine, University of Southampton and the Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK.
¹⁴ Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London SE1 9RT, UK.
¹⁵ Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast BT9 7AB, UK.
¹⁶ 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.
¹⁷ Northern Genetics Service, Institute of Genetics Medicine, Newcastle upon Tyne NE1 3BZ, UK.
¹⁸ 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.
¹⁹ 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.
²⁰ PreventionGenetics, Marshfield, WI 54449, USA.
²¹ Department of Human Genetics, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama 236-0004, Japan.
²² Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka 594-1101, Japan.
²³ 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.
²⁴ Laboratorio di Genetica Medica, ASST Papa Giovanni XXIII, Piazza OMS 1, 24127 Bergamo, Italy.
²⁵ Dipartimento Pediatria, University of Padova, Via Giustiani 3, 35128 Padova, Italy.
²⁶ Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, Canada; The Stollery Pediatric Hospital, Edmonton, AB T6G 2H7, Canada.
²⁷ 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.
²⁸ 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.
²⁹ 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.
³⁰ 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.
³¹ 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. Electronic address: [email protected].

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.

Keywords: DNA methylation signature; EED; SUZ12; intellectual disability; overgrowth syndromes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Abnormalities, Multiple / genetics*
Adolescent
Adult
Child
Child, Preschool
Cohort Studies
Congenital Hypothyroidism / genetics*
Craniofacial Abnormalities / genetics*
DNA Methylation*
Enhancer of Zeste Homolog 2 Protein / genetics*
Female
Hand Deformities, Congenital / genetics*
Humans
Infant
Intellectual Disability / genetics*
Male
Mosaicism
Mutation*
Mutation, Missense / genetics
Neoplasm Proteins
Polycomb Repressive Complex 2 / genetics*
Reproducibility of Results
Transcription Factors
Young Adult

Substances

EED protein, human
Neoplasm Proteins
SUZ12 protein, human
Transcription Factors
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Polycomb Repressive Complex 2

Supplementary concepts

Weaver syndrome

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding