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M\u00f8ller Fonden","doi-asserted-by":"publisher","award":["20\u2010L\u20100371"],"award-info":[{"award-number":["20\u2010L\u20100371"]}],"id":[{"id":"10.13039\/501100005747","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007438","name":"Familien Hede Nielsens Fond","doi-asserted-by":"publisher","award":["2021\u2010 0010"],"award-info":[{"award-number":["2021\u2010 0010"]}],"id":[{"id":"10.13039\/501100007438","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["Ricerca Corrente 2021"],"award-info":[{"award-number":["Ricerca Corrente 2021"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["5x1000 2021"],"award-info":[{"award-number":["5x1000 2021"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["RCR\u20102020\u201023670068_001"],"award-info":[{"award-number":["RCR\u20102020\u201023670068_001"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Disease\u2010specific DNA methylation patterns (DNAm signatures) have been established for an increasing number of genetic disorders and represent a valuable tool for classification of genetic variants of uncertain significance (VUS). Sample size and batch effects are critical issues for establishing DNAm signatures, but their impact on the sensitivity and specificity of an already established DNAm signature has not previously been tested. Here, we assessed whether publicly available DNAm data can be employed to generate a binary machine learning classifier for VUS classification, and used variants in <jats:italic>KMT2D<\/jats:italic>, the gene associated with Kabuki syndrome, together with an existing DNAm signature as proof\u2010of\u2010concept. Using publicly available methylation data for training, a classifier for <jats:italic>KMT2D<\/jats:italic> variants was generated, and individuals with molecularly confirmed Kabuki syndrome and unaffected individuals could be correctly classified. The present study documents the clinical utility of a robust DNAm signature even for few affected individuals, and most importantly, underlines the importance of data sharing for improved diagnosis of rare genetic disorders.<\/jats:p>","DOI":"10.1111\/cge.14304","type":"journal-article","created":{"date-parts":[[2023,1,27]],"date-time":"2023-01-27T13:04:56Z","timestamp":1674824696000},"page":"688-692","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["<scp>DNA<\/scp> methylation signature classification of rare disorders using publicly available methylation data"],"prefix":"10.1111","volume":"103","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2016-3670","authenticated-orcid":false,"given":"Mathis","family":"Hildonen","sequence":"first","affiliation":[{"name":"Kennedy Center, Department of Clinical Genetics Copenhagen University Hospital, Rigshospitalet  Glostrup 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Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lotte","family":"Risom","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Copenhagen University Hospital, Rigshospitalet  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2762-1002","authenticated-orcid":false,"given":"Mads","family":"Bak","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Copenhagen University Hospital, Rigshospitalet  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jakob","family":"Ek","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Copenhagen University Hospital, Rigshospitalet  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9664-1448","authenticated-orcid":false,"given":"Rikke 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