title: NSD1 mutations generate a genome-wide DNA methylation signature.
abstract: Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1. As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1(+/-)-specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1(+/-) signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing.
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
authors.forename: S
authors.initials: S
authors.lastname: Choufani
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.|Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.|Department of Molecular Genetics, University of Toronto, 27 King's College Circle, Toronto, Ontario, Canada M5S 1A1.
authors.forename: C
authors.initials: C
authors.lastname: Cytrynbaum
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, 6/F, William MW Mong Block, 21 Sassoon Road, Pokfulam, Hong Kong.
authors.forename: B H Y
authors.initials: BH
authors.lastname: Chung
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.|Centre for Computational Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
authors.forename: A L
authors.initials: AL
authors.lastname: Turinsky
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
authors.forename: D
authors.initials: D
authors.lastname: Grafodatskaya
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.|Institute of Medical Science, School of Graduate Studies, University of Toronto, 2374-1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Y A
authors.initials: YA
authors.lastname: Chen
authors.affiliation: Department of Medical Genetics, UBC, Child and Family Research Institute, 950W 28th Avenue, Vancouver, British Columbia V5Z 4H4, USA.
authors.forename: A S A
authors.initials: AS
authors.lastname: Cohen
authors.affiliation: Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.|Department of Molecular Genetics, University of Toronto, 27 King's College Circle, Toronto, Ontario, Canada M5S 1A1.
authors.forename: L
authors.initials: L
authors.lastname: Dupuis
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
authors.forename: D T
authors.initials: DT
authors.lastname: Butcher
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
authors.forename: M T
authors.initials: MT
authors.lastname: Siu
authors.affiliation: Clinical Genetics Service, Department of Health, Cheung Sha Wan Jockey Club Clinic, 1/F-3/F, 2 Kwong Lee Road, Sham Shui Po, Kowloon, Hong Kong.
authors.forename: H M
authors.initials: HM
authors.lastname: Luk
authors.affiliation: Clinical Genetics Service, Department of Health, Cheung Sha Wan Jockey Club Clinic, 1/F-3/F, 2 Kwong Lee Road, Sham Shui Po, Kowloon, Hong Kong.
authors.forename: I F M
authors.initials: IF
authors.lastname: Lo
authors.affiliation: Clinical Genetics Service, Department of Health, Cheung Sha Wan Jockey Club Clinic, 1/F-3/F, 2 Kwong Lee Road, Sham Shui Po, Kowloon, Hong Kong.
authors.forename: S T S
authors.initials: ST
authors.lastname: Lam
authors.affiliation: Department of Medical Genetics, University of Alberta, 116 Street and 85 Avenue, Edmonton, Alberta, Canada T6G 2R3.
authors.forename: O
authors.initials: O
authors.lastname: Caluseriu
authors.affiliation: Pediatric Laboratory Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.|Laboratory Medicine and Pathobiology, University of Toronto, 27 King's College Circle, Toronto, Ontario, Canada M5S 1A1.
authors.forename: D J
authors.initials: DJ
authors.lastname: Stavropoulos
authors.affiliation: Our Lady's Hospital for Sick Children, Crumlin D12 N512 Ireland.
authors.forename: W
authors.initials: W
authors.lastname: Reardon
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.|Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.|Department of Pediatrics, University of Toronto, 27 King's College Circle, Toronto, Ontario, Canada M5S 1A1.
authors.forename: R
authors.identifier: http://orcid.org/0000-0003-3542-8106
authors.initials: R
authors.lastname: Mendoza-Londono
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.|Centre for Computational Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.|Department of Computer Science, University of Toronto, 27 King's College Circle, Toronto, Ontario, Canada M5S 1A1.
authors.forename: M
authors.initials: M
authors.lastname: Brudno
authors.affiliation: Department of Medical Genetics, UBC, Child and Family Research Institute, 950W 28th Avenue, Vancouver, British Columbia V5Z 4H4, USA.
authors.forename: W T
authors.initials: WT
authors.lastname: Gibson
authors.affiliation: Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.|Department of Molecular Genetics, University of Toronto, 27 King's College Circle, Toronto, Ontario, Canada M5S 1A1.|Department of Pediatrics, University of Toronto, 27 King's College Circle, Toronto, Ontario, Canada M5S 1A1.|Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5.
authors.forename: D
authors.initials: D
authors.lastname: Chitayat
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.|Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.|Department of Molecular Genetics, University of Toronto, 27 King's College Circle, Toronto, Ontario, Canada M5S 1A1.|Institute of Medical Science, School of Graduate Studies, University of Toronto, 2374-1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.|Department of Pediatrics, University of Toronto, 27 King's College Circle, Toronto, Ontario, Canada M5S 1A1.
authors.forename: R
authors.initials: R
authors.lastname: Weksberg
mesh_terms: D019175:DNA Methylation / Q000235:genetics*; D005786:Gene Expression Regulation; D015894:Genome, Human; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D058495:Sotos Syndrome / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C113272:NSD1 protein, human