{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T15:09:22Z","timestamp":1790694562673,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,2,5]],"date-time":"2022-02-05T00:00:00Z","timestamp":1644019200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"London Health Sciences Molecular Diagnostics Development Fund and Genome Canada Genomic Applications Partnership Program Grant","award":["Beyond Genomics: Assessing the Improvement in Diagnosis of Rare Diseases using Clinical Epigenomics in Canada, EpiSign-CAN"],"award-info":[{"award-number":["Beyond Genomics: Assessing the Improvement in Diagnosis of Rare Diseases using Clinical Epigenomics in Canada, EpiSign-CAN"]}]},{"name":"Italian Ministry of Health","award":["CCR-2017-23669081"],"award-info":[{"award-number":["CCR-2017-23669081"]}]},{"name":"Italian Ministry of Health","award":["RCR-2020-23670068_001"],"award-info":[{"award-number":["RCR-2020-23670068_001"]}]},{"name":"Italian Ministry of Health","award":["Ricerca Corrente 2021"],"award-info":[{"award-number":["Ricerca Corrente 2021"]}]},{"name":"Italian Ministry of Research","award":["FOE 2019"],"award-info":[{"award-number":["FOE 2019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Wiedemann\u2013Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.<\/jats:p>","DOI":"10.3390\/ijms23031815","type":"journal-article","created":{"date-parts":[[2022,2,6]],"date-time":"2022-02-06T20:36:47Z","timestamp":1644179807000},"page":"1815","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3021-7377","authenticated-orcid":false,"given":"Aidin","family":"Foroutan","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada"},{"name":"Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0400-2578","authenticated-orcid":false,"given":"Sadegheh","family":"Haghshenas","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada"},{"name":"Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratibha","family":"Bhai","sequence":"additional","affiliation":[{"name":"Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Levy","sequence":"additional","affiliation":[{"name":"Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1245-6606","authenticated-orcid":false,"given":"Jennifer","family":"Kerkhof","sequence":"additional","affiliation":[{"name":"Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haley","family":"McConkey","sequence":"additional","affiliation":[{"name":"Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4766-7753","authenticated-orcid":false,"given":"Marcello","family":"Niceta","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Ciolfi","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Pedace","sequence":"additional","affiliation":[{"name":"Department of Pediatric Onco-Hematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4747-1032","authenticated-orcid":false,"given":"Evelina","family":"Miele","sequence":"additional","affiliation":[{"name":"Department of Pediatric Onco-Hematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Genevieve","sequence":"additional","affiliation":[{"name":"Medical Genetic Department for Rare Diseases and Personalized Medicine, Reference Center AD SOOR, AnDDI-RARE, Groupe DI, Inserm U1183\u2014Institute for Regenerative Medicine and Biotherapy, Montpellier University, Centre Hospitalier Universitaire de Montpellier, 34090 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solveig","family":"Heide","sequence":"additional","affiliation":[{"name":"Department of Genetics, Referral Center for Intellectual Disabilities, APHP Sorbonne University, Piti\u00e9 Salp\u00eatri\u00e8re Hospital, 75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari\u00eblle","family":"Alders","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Zampino","sequence":"additional","affiliation":[{"name":"Center for Rare Diseases and Congenital Defects, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy"},{"name":"Facolt\u00e0 di Medicina e Chirurgia, Universit\u00e0 Cattolica del S. Cuore, 20123 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5078-928X","authenticated-orcid":false,"given":"Giuseppe","family":"Merla","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnology, Universit\u00e0 di Napoli \u201cFederico II\u201d, 80131 Naples, Italy"},{"name":"Laboratory of Regulatory and Functional Genomics, Fondazione Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9lanie","family":"Fradin","sequence":"additional","affiliation":[{"name":"Service de G\u00e9n\u00e9tique, CHU de Rennes, 35203 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Bieth","sequence":"additional","affiliation":[{"name":"Medical Genetics Department, University of Angers, CHU Angers, 49000 Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Bonneau","sequence":"additional","affiliation":[{"name":"Department of genetics, CHU d\u2019Angers, 49000 Angers, France and MitoVasc, UMR CNRS 6015-INSERM 1083, University of Angers, 49055 Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4362-4062","authenticated-orcid":false,"given":"Klaus","family":"Dieterich","sequence":"additional","affiliation":[{"name":"CHU Grenoble Alpes, Inserm, U1209, Institute of Advanced Biosciences, Universit\u00e9 Grenoble Alpes, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Fergelot","sequence":"additional","affiliation":[{"name":"Medical Genetics Department, Inserm U1211, Reference Center AD SOOR, AnDDI-RARE, Bordeaux University, Centre Hospitalier Universitaire de Bordeaux, 33076 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1004-6814","authenticated-orcid":false,"given":"Elise","family":"Schaefer","sequence":"additional","affiliation":[{"name":"Service de G\u00e9n\u00e9tique M\u00e9dicale\u2014Institut de G\u00e9n\u00e9tique M\u00e9dicale d\u2019Alsace\u2014H\u00f4pitaux Universitaires de Strasbourg, 67091 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Faivre","sequence":"additional","affiliation":[{"name":"Inserm, UMR1231, Equipe GAD, B\u00e2timent B3, Universit\u00e9 de Bourgogne Franche Comt\u00e9, 15 boulevard du Mar\u00e9chal de Lattre de Tassigny, 21000 Dijon, France"},{"name":"Unit\u00e9 Fonctionnelle Innovation en Diagnostic G\u00e9nomique des Maladies Rares, FHU-TRANSLAD, Department of Medical Genetics, Dijon University Hospital, 21000 Dijon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3717-8374","authenticated-orcid":false,"given":"Antonio","family":"Vitobello","sequence":"additional","affiliation":[{"name":"Inserm, UMR1231, Equipe GAD, B\u00e2timent B3, Universit\u00e9 de Bourgogne Franche Comt\u00e9, 15 boulevard du Mar\u00e9chal de Lattre de Tassigny, 21000 Dijon, France"},{"name":"Unit\u00e9 Fonctionnelle Innovation en Diagnostic G\u00e9nomique des Maladies Rares, FHU-TRANSLAD, Department of Medical Genetics, Dijon University Hospital, 21000 Dijon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Maitz","sequence":"additional","affiliation":[{"name":"Clinical Pediatric Genetics Unit, Pediatrics Clinics, MBBM Foundation, S. Gerardo Hospital, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Fischetto","sequence":"additional","affiliation":[{"name":"Clinical Genetics Unit, Department of Pediatric Medicine, Giovanni XXIII Children\u2019s Hospital, 02115 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1165-7935","authenticated-orcid":false,"given":"Cristina","family":"Gervasini","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Piccione","sequence":"additional","affiliation":[{"name":"Department of Sciences for Health Promotion and Mother and Child Care \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2523-1230","authenticated-orcid":false,"given":"Ingrid","family":"van de Laar","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7736-9672","authenticated-orcid":false,"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bekim","family":"Sadikovic","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada"},{"name":"Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7519-9822","authenticated-orcid":false,"given":"Anne-Sophie","family":"Lebre","sequence":"additional","affiliation":[{"name":"Team Physiopathologie des Maladies Psychiatriques, GDR3557-Institut de Psychiatrie, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Universit\u00e9 de Paris, 75006 Paris, France"},{"name":"Centre Hospitalier Universitaire de Reims, P\u00f4le de Biologie M\u00e9dicale et Pathologie, Service de G\u00e9n\u00e9Tique, 51100 Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.ejmg.2017.03.006","article-title":"Wiedemann-Steiner syndrome: Novel pathogenic variant and review of literature","volume":"60","author":"Aggarwal","year":"2017","journal-title":"Eur. 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