ArticleAmerican journal of human genetics2020
DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes.
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Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.
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52 citing papers in PubMed, 1 synthesis or guideline pooled it, 80 citations in OpenAlex.
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Authors and funding
38 authors at 20 institutions in 9 countries.
Sanaa ChoufaniGenetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
William T GibsonBritish 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 TurinskyGenetics 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 ChungPediatrics and Adolescent Medicine, Queen Mary Hospital and Hong Kong Children's Hospital, The University of Hong Kong, 999077 Hong Kong.
Tianren WangGenetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Kopal GargGenetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Alessandro VitrioloDepartment 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 CohenBritish 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 CyrusBritish 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 GoodmanGenetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Eric Chater-DiehlGenetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Jack BrzezinskiGenetics 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 BrudnoGenetics 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 MingClinical Genetic Service, Department of Health, 999077 Hong Kong.
Susan M WhiteVictorian Clinical Genetics Service, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
Sally Ann LynchDepartment of Clinical Genetics, Temple Street Children's University Hospital, Dublin, D01 XD99, Ireland.
Carol ClericuzioPediatric Genetics, University of New Mexico, Albuquerque, NM 87131, USA.
I Karen TempleFaculty of Medicine, University of Southampton and the Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK.
Frances FlinterDepartment of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London SE1 9RT, UK.
Vivienne McConnellNorthern Ireland Regional Genetics Service, Belfast City Hospital, Belfast BT9 7AB, UK.
Tom CushingPediatric Genetics, University of New Mexico, Albuquerque, NM 87131, USA.
Lynne M BirdDepartment 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 SplittNorthern Genetics Service, Institute of Genetics Medicine, Newcastle upon Tyne NE1 3BZ, UK.
Bronwyn KerrDivision 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 SchererGenetics 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 MachadoPreventionGenetics, Marshfield, WI 54449, USA.
Eri ImagawaDepartment of Human Genetics, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama 236-0004, Japan.
Nobuhiko OkamotoDepartment of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka 594-1101, Japan.
Naomichi MatsumotoDepartment of Human Genetics, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama 236-0004, Japan.
Guiseppe TestaDepartment 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 IasconeLaboratorio di Genetica Medica, ASST Papa Giovanni XXIII, Piazza OMS 1, 24127 Bergamo, Italy.
Romano TenconiDipartimento Pediatria, University of Padova, Via Giustiani 3, 35128 Padova, Italy.
Oana CaluseriuDepartment of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, Canada; The Stollery Pediatric Hospital, Edmonton, AB T6G 2H7, Canada.
Roberto Mendoza-LondonoDivision 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 ChitayatDivision 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 CytrynbaumGenetics 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-BrownSt 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 WeksbergGenetics 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: rweksb@sickkids.ca.
Hospital for Sick Children · CAUniversity of British Columbia · CAUniversity of Toronto · CAUniversity of New Mexico · USYokohama City University · JPBelfast City Hospital · GBDepartment of Health · CNGuy's and St Thomas' NHS Foundation Trust · GBHuman Technopole · ITInstitute of Genetics and Cancer · GBManchester Academic Health Science Centre · GBMurdoch Children's Research Institute · AUOsaka International Cancer Institute · JPOspedale Papa Giovanni XXIII · ITQueen Mary Hospital · CNSt George's, University of London · GBTemple Street Children's University Hospital · IEUniversity Hospital Southampton NHS Foundation Trust · GBUniversity of Alberta · CAUniversity of California San Diego · US
Funding
CIHR IGH-155182CIHR MOP-126054CIHR PJT-148830
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.
Indexed as
DNA MethylationMutationAbnormalities, MultipleAdolescentAdultChildChild, PreschoolCohort StudiesCongenital HypothyroidismCraniofacial AbnormalitiesEnhancer of Zeste Homolog 2 ProteinFemaleHand Deformities, CongenitalHumansInfantIntellectual DisabilityEED protein, humanEnhancer of Zeste Homolog 2 ProteinEZH2 protein, humanNeoplasm ProteinsPolycomb Repressive Complex 2SUZ12 protein, humanTranscription FactorsDNA methylation signatureEEDintellectual disabilityovergrowth syndromesSUZ12
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