{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T07:58:26Z","timestamp":1790755106393,"version":"4.1.0"},"reference-count":51,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS127830"],"award-info":[{"award-number":["R01NS127830"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS131512"],"award-info":[{"award-number":["R01NS131512"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["U24NS120854"],"award-info":[{"award-number":["U24NS120854"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      <jats:italic>STXBP1<\/jats:italic>\n                      \u2010related disorders (\n                      <jats:italic>STXBP1<\/jats:italic>\n                      \u2010RD) are among the most common genetic neurodevelopmental disorders, marked by early onset epilepsy, global developmental delay, and motor impairments. Many missense variants remain uncharacterized, limiting accurate variant interpretation and hindering development of precision therapies. Current American College of Medical Genetics and Genomics (ACMG)\/Association for Molecular Pathology (AMP) variant curation frameworks provide limited discriminatory power for\n                      <jats:italic>STXBP1<\/jats:italic>\n                      missense variants due to limited functional data and frequently incomplete parental testing, leaving a substantial proportion of variants classified as variants of uncertain significance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We developed a fluorometric assay that leverages split fluorescence complementation to simultaneously measure STXBP1 protein stability and its binding affinity to a primary interaction partner, syntaxin\u20101A (STX1A), including genetically engineered closed and open STX1A conformations, which are essential for SNARE complex function. Using this platform, we evaluated five benign variants, six pathogenic variants, and four variants that result in an atypically mild clinical presentation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Benign population variants showed minimal effects on stability or binding, whereas known pathogenic variants consistently demonstrated reduced protein stability and diminished binding to STX1A, with some exhibiting STX1A conformation\u2010specific binding deficits. Variants associated with atypically mild phenotypes displayed intermediate, variant\u2010specific profiles. To quantify discriminatory performance, we developed and trained an exploratory support vector machine classifier using stability and binding metrics. With the exception of a single\n                      <jats:italic>STXBP1<\/jats:italic>\n                      variant in an individual with a mild clinical presentation, the model correctly classified benign and pathogenic variants using leave\u2010one\u2010out cross\u2010validation. For variants with available clinical data, classifier scores showed a statistically significant correlation with clinical severity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>\n                      Together, these findings demonstrate that a scalable, quantitative assay capturing STXBP1 stability and syntaxin\u2010binding behavior can differentiate benign from pathogenic variants and provide functional insights into mechanisms of pathogenicity. This platform offers a path toward improved variant interpretation, supports refinement of ACMG\/AMP criteria for synaptic disorders, and may inform future therapeutic targeting strategies for\n                      <jats:italic>STXBP1<\/jats:italic>\n                      \u2010RD.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi.70504","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T07:16:30Z","timestamp":1790752590000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional profiling of\n                    <scp>\n                      <i>STXBP1<\/i>\n                    <\/scp>\n                    missense variants using a novel dual\u2010readout fluorometric assay"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4562-7969","authenticated-orcid":false,"given":"Elisa A.","family":"Waxman","sequence":"first","affiliation":[{"name":"Center for Cellular and Molecular Therapeutics Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Center for Epilepsy and Neurodevelopmental Disorders, Children's Hospital of Philadelphia University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1293-640X","authenticated-orcid":false,"given":"Jennine M.","family":"Dawicki\u2010McKenna","sequence":"additional","affiliation":[{"name":"Center for Epilepsy and Neurodevelopmental Disorders, Children's Hospital of Philadelphia University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"},{"name":"Department of Physiology University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9131-4847","authenticated-orcid":false,"given":"Ian","family":"McSalley","sequence":"additional","affiliation":[{"name":"Center for Epilepsy and Neurodevelopmental Disorders, Children's Hospital of Philadelphia University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"},{"name":"Division of Neurology Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Epilepsy NeuroGenetics Initiative Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7459-1778","authenticated-orcid":false,"given":"Anna J.","family":"Prentice","sequence":"additional","affiliation":[{"name":"Center for Epilepsy and Neurodevelopmental Disorders, Children's Hospital of Philadelphia University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"},{"name":"Division of Neurology Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Epilepsy NeuroGenetics Initiative Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0170-3615","authenticated-orcid":false,"given":"Torrey A.","family":"Chisari","sequence":"additional","affiliation":[{"name":"Center for Epilepsy and Neurodevelopmental Disorders, Children's Hospital of Philadelphia University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"},{"name":"Division of Neurology Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Epilepsy NeuroGenetics Initiative Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0834-0750","authenticated-orcid":false,"given":"Sarah M.","family":"Ruggiero","sequence":"additional","affiliation":[{"name":"Center for Epilepsy and Neurodevelopmental Disorders, Children's Hospital of Philadelphia University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"},{"name":"Division of Neurology Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Epilepsy NeuroGenetics Initiative Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9724-0403","authenticated-orcid":false,"given":"Jillian L.","family":"McKee","sequence":"additional","affiliation":[{"name":"Center for Epilepsy and Neurodevelopmental Disorders, Children's Hospital of Philadelphia University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"},{"name":"Division of Neurology Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Epilepsy NeuroGenetics Initiative Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Department of Biomedical and Health Informatics Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Department of Neurology University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7145-7169","authenticated-orcid":false,"given":"Alex J.","family":"Felix","sequence":"additional","affiliation":[{"name":"Center for Epilepsy and Neurodevelopmental Disorders, Children's Hospital of Philadelphia University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"},{"name":"Department of Physiology University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2522-2684","authenticated-orcid":false,"given":"Giulia","family":"Pavani","sequence":"additional","affiliation":[{"name":"Center for Cellular and Molecular Therapeutics Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Center for Epilepsy and Neurodevelopmental Disorders, Children's Hospital of Philadelphia University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"},{"name":"Department of Pathology and Laboratory Medicine University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3696-9131","authenticated-orcid":false,"given":"Benjamin L.","family":"Prosser","sequence":"additional","affiliation":[{"name":"Center for Epilepsy and Neurodevelopmental Disorders, Children's Hospital of Philadelphia University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"},{"name":"Department of Physiology University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5649-9603","authenticated-orcid":false,"given":"Michael J.","family":"Boland","sequence":"additional","affiliation":[{"name":"Center for Epilepsy and Neurodevelopmental Disorders, Children's Hospital of Philadelphia University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"},{"name":"Department of Physiology University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8486-0558","authenticated-orcid":false,"given":"Ingo","family":"Helbig","sequence":"additional","affiliation":[{"name":"Center for Epilepsy and Neurodevelopmental Disorders, Children's Hospital of Philadelphia University of Pennsylvania Perelman 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