{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T20:56:15Z","timestamp":1780433775867,"version":"3.54.1"},"reference-count":27,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,19]],"date-time":"2022-11-19T00:00:00Z","timestamp":1668816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["Ricerca 5x1000_2019"],"award-info":[{"award-number":["Ricerca 5x1000_2019"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["RCR-2020-23670068_001"],"award-info":[{"award-number":["RCR-2020-23670068_001"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["RCR-2022-23682289"],"award-info":[{"award-number":["RCR-2022-23682289"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["RF-2018-12366931"],"award-info":[{"award-number":["RF-2018-12366931"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["FOE 2019"],"award-info":[{"award-number":["FOE 2019"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Italian Ministry of Research","award":["Ricerca 5x1000_2019"],"award-info":[{"award-number":["Ricerca 5x1000_2019"]}]},{"name":"Italian Ministry of Research","award":["RCR-2020-23670068_001"],"award-info":[{"award-number":["RCR-2020-23670068_001"]}]},{"name":"Italian Ministry of Research","award":["RCR-2022-23682289"],"award-info":[{"award-number":["RCR-2022-23682289"]}]},{"name":"Italian Ministry of Research","award":["RF-2018-12366931"],"award-info":[{"award-number":["RF-2018-12366931"]}]},{"name":"Italian Ministry of Research","award":["FOE 2019"],"award-info":[{"award-number":["FOE 2019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Inactivating NSD1 mutations causing Sotos syndrome have been previously associated with a specific genome-wide DNA methylation (DNAm) pattern. Sotos syndrome is characterized by phenotypic overlap with other overgrowth syndromes, and a definite diagnosis might not be easily reached due to the high prevalence of variants of unknown significance (VoUS) that are identified in patients with a suggestive phenotype. Objective: we performed microarray DNAm profiling in a set of 11 individuals with a clinical suspicion of Sotos syndrome and carrying an NSD1 VoUS or previously unreported variants to solve uncertainty in defining pathogenicity of the observed variants. The impact of the training cohort size on sensitivity and prediction confidence of the classifier was assessed. Results: The Sotos syndrome-specific DNAm signature was validated in six individuals with a clinical diagnosis of Sotos syndrome and carrying bona fide pathogenic NSD1 variants. Applying this approach to the remaining 11 individuals with NSD1 variants, we succeeded in confirming pathogenicity in eight subjects and excluding the diagnosis of Sotos syndrome in three. The sensitivity and prediction confidence of the classifier based on the different sizes of the training sets did not show substantial differences, though the overall performance was improved by using a data balancing strategy. Conclusions: The present approach solved uncertainty in cases with NDS1 VoUS, further demonstrating the clinical utility of DNAm profiling.<\/jats:p>","DOI":"10.3390\/genes13112163","type":"journal-article","created":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T03:09:30Z","timestamp":1669000170000},"page":"2163","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Genome-Wide DNA Methylation Profiling Solves Uncertainty in Classifying NSD1 Variants"],"prefix":"10.3390","volume":"13","author":[{"given":"Marco","family":"Ferilli","sequence":"first","affiliation":[{"name":"Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6191-0978","authenticated-orcid":false,"given":"Andrea","family":"Ciolfi","sequence":"additional","affiliation":[{"name":"Area di Ricerca Genetica e Malattie Rare, 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-Haematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4766-7753","authenticated-orcid":false,"given":"Marcello","family":"Niceta","sequence":"additional","affiliation":[{"name":"Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1993-8018","authenticated-orcid":false,"given":"Francesca Clementina","family":"Radio","sequence":"additional","affiliation":[{"name":"Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Pizzi","sequence":"additional","affiliation":[{"name":"Area di Ricerca Genetica e Malattie Rare, 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-Haematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Cappelletti","sequence":"additional","affiliation":[{"name":"Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Mancini","sequence":"additional","affiliation":[{"name":"Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Galluccio","sequence":"additional","affiliation":[{"name":"Department of Pediatric Onco-Haematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Andreani","sequence":"additional","affiliation":[{"name":"Department of Pediatric Onco-Haematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4707-212X","authenticated-orcid":false,"given":"Maria","family":"Iascone","sequence":"additional","affiliation":[{"name":"Medical Genetics Laboratory, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Chiriatti","sequence":"additional","affiliation":[{"name":"Unit\u00e0 di Genetica Medica, Grande Ospedale Metropolitano \u201cBianchi-Melacrino-Morelli\u201d, 89124 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9037-4297","authenticated-orcid":false,"given":"Antonio","family":"Novelli","sequence":"additional","affiliation":[{"name":"Translational Cytogenomics Research Unit, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, 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Garofolo, 34137 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Prontera","sequence":"additional","affiliation":[{"name":"Maternal-Infantile Department, University Hospital of Perugia, 06156 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alba","family":"Pilotta","sequence":"additional","affiliation":[{"name":"Auxo-Endocrinology, Diabetology and Medical Genetic Unit, Department of Paediatrics, ASST Spedali Civili, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6723-9177","authenticated-orcid":false,"given":"Maria Francesca","family":"Bedeschi","sequence":"additional","affiliation":[{"name":"Medical Genetic Unit, Fondazione IRCCS C\u00e0 Granda Ospedale Maggiore Policlinico Clinica Mangiagalli, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Capolino","sequence":"additional","affiliation":[{"name":"Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anwar","family":"Baban","sequence":"additional","affiliation":[{"name":"Medical and Surgical Department of Pediatric Cardiology, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2425-2176","authenticated-orcid":false,"given":"Marco","family":"Seri","sequence":"additional","affiliation":[{"name":"U.O. 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Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1086\/345647","article-title":"NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes","volume":"72","author":"Douglas","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/sj.ejhg.5201686","article-title":"Sotos syndrome","volume":"15","author":"Rahman","year":"2007","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_7","unstructured":"Adam, M.P., Everman, D.B., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., and Amemiya, A. (1993\u20132022). Sotos Syndrome. 2004 [Updated 2019 Aug 1]. GeneReviews\u00ae [Internet], University of Washington. 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