{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:54:51Z","timestamp":1791219291034,"version":"4.1.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009020","name":"University of South China","doi-asserted-by":"publisher","award":["20224310NHYCG11"],"award-info":[{"award-number":["20224310NHYCG11"]}],"id":[{"id":"10.13039\/501100009020","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Variants in\n                      <jats:italic>SCN3A<\/jats:italic>\n                      gene encoding the voltage-gated sodium channel Nav1. 3 have been associated with severe developmental and\/or epileptic encephalopathies, characterized by early-onset, drug-resistant seizures, malformations of cortical development, and profound neurodevelopmental impairment. Rapid clinical interpretation of\n                      <jats:italic>SCN3A<\/jats:italic>\n                      missense variants remains challenging. This study aimed to explore potentially reliable indicators in reflecting the pathogenicity of\n                      <jats:italic>SCN3A<\/jats:italic>\n                      variants, thereby promoting genetic diagnosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The disease-associated and benign\/likely benign\n                      <jats:italic>SCN3A<\/jats:italic>\n                      missense variants were systematically collected via two independent epilepsy geneticists to curate high-confidence dataset. The molecular subregional effects were analyzed to explore possible genotype-phenotype correlation. The diagnostic performance of nineteen commonly used algorithms was systematically evaluated using ROC analysis and confusion matrices metrics such as accuracy, sensitivity, specificity, and Matthews correlation coefficient (MCC).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 20 pathogenic, affecting 37 patients, and 45 benign\/likely benign\n                      <jats:italic>SCN3A<\/jats:italic>\n                      variants were included. Pathogenic\n                      <jats:italic>SCN3A<\/jats:italic>\n                      variants were statistically more located in transmembrane regions than in other regions, suggesting possible subregional effects. Deep-learning-based tools incorporating structural data, AlphaMissense, demonstrated superior balanced accuracy (&amp;gt;90%) and robust discrimination (AUC &amp;gt; 0.96). Meta-predictors, such as BayesDel_addAF and ClinPred, also showed high sensitivity but lower specificity at default thresholds. Notably, applying gene-specific optimal thresholds significantly improved performance across multiple tools.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study provides systematic benchmarks for algorithms in\n                      <jats:italic>SCN3A<\/jats:italic>\n                      -related DEEs. Integration of reliable algorithms with gene-specific thresholds into clinical variant interpretation pipelines could possibly refine the pathogenicity assessment of missense variants, subsequently informing timely risk stratification and personalized therapeutic strategies for affected patients.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1772239","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T05:22:26Z","timestamp":1770268946000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Toward precision medicine in SCN3A variants-associated encephalopathies and epilepsy: optimizing genetic diagnosis and molecular subregional effects"],"prefix":"10.3389","volume":"17","author":[{"given":"Peng-Yu","family":"Wang","sequence":"first","affiliation":[{"name":"The Affiliated Nanhua Hospital, Department of Neurology, Hengyang Medical School, University of South China","place":["Hengyang, China"]},{"name":"Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Xing","family":"Zhao","sequence":"additional","affiliation":[{"name":"The Affiliated Nanhua Hospital, Department of Neurology, Hengyang Medical School, University of South China","place":["Hengyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Hui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology, The First Affiliated Hospital & Clinical Neuroscience Institute of Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Jun","family":"Chen","sequence":"additional","affiliation":[{"name":"The Affiliated Nanhua Hospital, Department of Neurology, Hengyang Medical School, University of South China","place":["Hengyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, Department of Neurology, Hengyang Medical School, University of South China","place":["Hengyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1111\/j.1528-1167.2010.02522.x","article-title":"Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 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