{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T16:13:40Z","timestamp":1789661620319,"version":"4.0.1"},"reference-count":0,"publisher":"American Society for Clinical Investigation","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NINDS","award":["U54 NS117170"],"award-info":[{"award-number":["U54 NS117170"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    <jats:italic>STXBP1<\/jats:italic>\n                    variants are a frequent cause of early-onset developmental and epileptic encephalopathies and related neurodevelopmental disorders, but the clinical interpretation of these variants remains a major challenge. Most reported\n                    <jats:italic>STXBP1<\/jats:italic>\n                    missense variants are classified as variants of uncertain significance (VUS), complicating diagnosis, counseling, and patient eligibility for precision therapies. Here, we developed EpiPred, a gene-specific machine learning classifier that predicts the pathogenicity of\n                    <jats:italic>STXBP1<\/jats:italic>\n                    missense variants and tests these predictions using empirical evidence from well-established cellular assays. Trained on a curated set of pathogenic and benign variants, EpiPred outperformed global prediction tools in accuracy, sensitivity, and specificity. We validated the model\u2019s predictions using variant effect assays that measure protein abundance, solubility, stability, and interaction with the SNARE complex partner syntaxin 1. These biochemical readouts aligned closely with model outputs and enabled reclassification of several possibly misdiagnosed variants, which warrant further validation and clinical reevaluation. We deployed EpiPred in an interactive web application that allows clinicians, researchers, and patients to explore predictions for all possible STXBP1 missense variants. By identifying likely pathogenic\n                    <jats:italic>STXBP1<\/jats:italic>\n                    variants, including those that may respond to emerging therapies such as protein stabilizers. By coupling gene-calibrated machine learning with orthogonal variant-effect assays and public deployment, EpiPred provides a transferable framework for VUS resolution, trial enrichment, and precision diagnosis across clinically actionable Mendelian disease genes.\n                  <\/jats:p>","DOI":"10.1172\/jci207160","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T16:00:17Z","timestamp":1789660817000},"source":"Crossref","is-referenced-by-count":0,"title":["Gene-specific machine learning model EpiPred identifies likely pathogenic variants in the epilepsy-related gene STXBP1"],"prefix":"10.1172","author":[{"given":"Jeffrey D.","family":"Calhoun","sequence":"first","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengbing","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carina G.","family":"Biar","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan R.","family":"Gunti","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John S.","family":"Lee","sequence":"additional","affiliation":[{"name":"Northwestern IT Research Computing and Data Services, Evanston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron M.","family":"Geller","sequence":"additional","affiliation":[{"name":"Northwestern IT Research Computing and Data Services, Evanston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung H.","family":"Hong","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Schnell","sequence":"additional","affiliation":[{"name":"Departments of Mathematics, Biochemistry & Cell Biology and Biomedical Data, Dartmouth College, Hanover, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis T.","family":"Dang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Michigan, Ann Arbor, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Michigan, Ann Arbor, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack M.","family":"Parent","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Michigan, Ann Arbor, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9479-6729","authenticated-orcid":true,"given":"Lori L.","family":"Isom","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Michigan, Ann Arbor, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Uhler","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry and Molecular Neuroscience Institute, University of Michigan, Ann Arbor, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather C.","family":"Mefford","sequence":"additional","affiliation":[{"name":"Center for Pediatric Neurological Disease Research, St. Jude Childen's Research Hospital, Memphis, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Elizabeth","family":"Ross","sequence":"additional","affiliation":[{"name":"Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Aguiar-Pulido","sequence":"additional","affiliation":[{"name":"Department of Computer Science, University of Miami, Miami, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma L.","family":"Carvill","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,9,17]]},"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.jci.org\/articles\/view\/207160\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T16:00:18Z","timestamp":1789660818000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.jci.org\/articles\/view\/207160"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,17]]},"references-count":0,"alternative-id":["10.1172\/JCI207160"],"URL":"https:\/\/doi.org\/10.1172\/jci207160","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,17]]}}}