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Fibroblast samples were cultured and analyzed using RNA sequencing to detect aberrant expression, aberrant splicing, and monoallelic expression using the Detection of RNA Outlier Pipeline (DROP) pipeline. Detected events were correlated with phenotypes, and long\u2010read genome sequencing was performed on individuals with strong candidate events to identify the causal genomic variant. A systematic literature review on RNA sequencing in rare disorders was conducted to contextualize our findings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      RNA sequencing identified five strong candidate events in four individuals, affecting the genes\n                      <jats:italic>QRICH1<\/jats:italic>\n                      ,\n                      <jats:italic>TSC1<\/jats:italic>\n                      ,\n                      <jats:italic>SMARCA1<\/jats:italic>\n                      ,\n                      <jats:italic>GNAI1<\/jats:italic>\n                      , and\n                      <jats:italic>PTEN<\/jats:italic>\n                      . (Likely) pathogenic genomic variants affecting expression of\n                      <jats:italic>QRICH1<\/jats:italic>\n                      ,\n                      <jats:italic>TSC1<\/jats:italic>\n                      , and\n                      <jats:italic>SMARCA1<\/jats:italic>\n                      were detected, resulting in a diagnostic yield of 7% (3\/41). Two variants were not covered in the initial exome sequencing data but were revealed through long\u2010read sequencing. The identification of a pathogenic\n                      <jats:italic>TSC1<\/jats:italic>\n                      variant led to a previously unrecognized diagnosis of tuberous sclerosis complex. This prompted guideline\u2010based screening, which revealed tuberous sclerosis lesions in the brain and lung, directly impacting clinical care. Notably, two of the three pathogenic events would not have been detected using whole blood due to the lack of expression of the involved genes. The lower yield of this study compared to studies in other rare disorders reflects the genetic heterogeneity of epilepsy and neurodevelopmental disorders, and the inaccessibility of affected tissue.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>This research underscores RNA sequencing of cultured fibroblasts as a valuable tool in genetic diagnostics for childhood onset epilepsy, particularly when conventional methods fail. Expanding the control dataset with age\u2010matched samples and incorporating RNA sequencing with nonsense\u2010mediated decay inhibition could further enhance diagnostic yield.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.18279","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T09:43:55Z","timestamp":1738143835000},"page":"1613-1627","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Fibroblast transcriptomics uncovers pathogenic genomic variants in individuals with exome\u2010negative childhood onset epilepsy"],"prefix":"10.1111","volume":"66","author":[{"given":"Noor","family":"Smal","sequence":"first","affiliation":[{"name":"Applied Translational Neurogenomics Group Vlaams Instituut voor Biotechnology (VIB) Center for Molecular Neurology, VIB  Antwerp Belgium"},{"name":"Applied Translational Neurogenomics Group, Department of Biomedical Sciences University of Antwerp  Antwerp Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charissa","family":"Millevert","sequence":"additional","affiliation":[{"name":"Applied Translational Neurogenomics Group Vlaams Instituut voor Biotechnology (VIB) Center for Molecular Neurology, VIB  Antwerp Belgium"},{"name":"Department of Neurology Antwerp University Hospital  Antwerp Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6422-210X","authenticated-orcid":false,"given":"Matthias","family":"De Wachter","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology, Department of Pediatrics Antwerp University Hospital  Antwerp Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Els","family":"De Vriendt","sequence":"additional","affiliation":[{"name":"Applied Translational Neurogenomics Group Vlaams Instituut voor Biotechnology (VIB) Center for Molecular Neurology, VIB  Antwerp Belgium"},{"name":"Applied Translational Neurogenomics Group, Department of Biomedical Sciences University of Antwerp  Antwerp Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9648-5984","authenticated-orcid":false,"given":"Zakaria","family":"Eddafir","sequence":"additional","affiliation":[{"name":"Applied Translational Neurogenomics Group Vlaams Instituut voor Biotechnology (VIB) Center for Molecular Neurology, VIB  Antwerp Belgium"},{"name":"Applied Translational Neurogenomics Group, Department of Biomedical Sciences University of Antwerp  Antwerp Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7545-518X","authenticated-orcid":false,"given":"An\u2010Sofie","family":"Schoonjans","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology, Department of Pediatrics Antwerp University Hospital  Antwerp Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4986-8006","authenticated-orcid":false,"given":"Allan","family":"Bayat","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Danish Epilepsy Center  Dianalund Denmark"},{"name":"Department of Regional Health Research University of Southern Denmark  Odense Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9664-1448","authenticated-orcid":false,"given":"Rikke Steensbjerre","family":"M\u00f8ller","sequence":"additional","affiliation":[{"name":"Department of Regional Health Research University of Southern Denmark  Odense Denmark"},{"name":"Department of Epilepsy Genetics and Personalized Medicine Danish Epilepsy Center  Dianalund Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6790-6251","authenticated-orcid":false,"given":"Davide","family":"Mei","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Medical Genetics Meyer Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)  Florence Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simona","family":"Balestrini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Medical Genetics Meyer Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)  Florence Italy"},{"name":"Neuroscience Department University of Florence  Florence Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renzo","family":"Guerrini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Medical Genetics Meyer Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)  Florence Italy"},{"name":"Neuroscience Department University of Florence  Florence Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marije E. 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