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Episignatures are utilized in molecular diagnostics and can clarify variants of uncertain significance. A growing number of disease genes, including epilepsy genes, exhibit robust and reproducible episignatures. However, whether <jats:italic>SCN1A<\/jats:italic>, the most prominent epilepsy gene, has one or more episignatures has not yet been determined. We generated genome\u2010wide DNA methylation data and performed episignature analysis on 64 individuals with Dravet syndrome due to pathogenic loss\u2010of\u2010function (LOF) variants in <jats:italic>SCN1A<\/jats:italic> and seven individuals with early infantile <jats:italic>SCN1A<\/jats:italic> developmental and epileptic encephalopathy due to pathogenic gain\u2010of\u2010function (GOF) variants in <jats:italic>SCN1A<\/jats:italic>, relative to a large reference database of controls and rare disease episignature\u2010positive cohorts. We analyzed all samples with LOF variants together and performed separate analyses for missense, nonsense, and GOF variant cohorts. A reproducible blood\u2010derived episignature was not evident in any of the cohorts using current analytical approaches and reference data.<\/jats:p>","DOI":"10.1111\/epi.18315","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T14:05:01Z","timestamp":1739282701000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<scp><i>SCN1A<\/i><\/scp> pathogenic variants do not have a distinctive blood\u2010derived <scp>DNA<\/scp> methylation signature"],"prefix":"10.1111","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0808-3475","authenticated-orcid":false,"given":"Christy W.","family":"LaFlamme","sequence":"first","affiliation":[{"name":"Department of Cell and Molecular Biology, Center for Pediatric Neurological Disease Research St. Jude Children's Research Hospital  Memphis Tennessee USA"},{"name":"Graduate School of Biomedical Sciences St. Jude Children's Research 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Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Stobo","sequence":"additional","affiliation":[{"name":"West of Scotland Centre for Genomic Medicine Queen Elizabeth University Hospital  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7691-9492","authenticated-orcid":false,"given":"Gaetan","family":"Lesca","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, member of the European Reference Network EpiCARE University Hospital of Lyon and Claude Bernard Lyon I University  Lyon France"},{"name":"Pathophysiology and Genetics of Neuron and Muscle, UCBL, CNRS UMR5261\u2014INSERM U1315  Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2141-4216","authenticated-orcid":false,"given":"Joseph D.","family":"Symonds","sequence":"additional","affiliation":[{"name":"School of Health and Wellbeing University of Glasgow  Glasgow UK"},{"name":"Paediatric Neurosciences Research Group Royal Hospital for Children  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Brunklaus","sequence":"additional","affiliation":[{"name":"School of Health and Wellbeing University of Glasgow  Glasgow UK"},{"name":"Paediatric Neurosciences Research Group Royal Hospital for Children  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5355-7115","authenticated-orcid":false,"given":"Lynette G.","family":"Sadleir","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Child Health University of Otago  Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid E.","family":"Scheffer","sequence":"additional","affiliation":[{"name":"Department of Medicine, Epilepsy Research Centre University of Melbourne, Austin Health  Heidelberg Victoria Australia"},{"name":"Department of Paediatrics University of Melbourne, Royal Children's Hospital  Melbourne Victoria Australia"},{"name":"Florey Institute and Murdoch Children's Research Institute  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bekim","family":"Sadikovic","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Western University  London Ontario Canada"},{"name":"Verspeeten Clinical Genome Centre London Health Science Centre  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7188-522X","authenticated-orcid":false,"given":"Heather C.","family":"Mefford","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology, Center for Pediatric Neurological Disease Research St. Jude Children's Research Hospital  Memphis Tennessee 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