{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T07:19:25Z","timestamp":1787901565641,"version":"build-2784847793"},"reference-count":61,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82471473"],"award-info":[{"award-number":["82471473"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32570722"],"award-info":[{"award-number":["32570722"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32370649"],"award-info":[{"award-number":["32370649"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2025A1515012437"],"award-info":[{"award-number":["2025A1515012437"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Pathogenic variants in\n                      <jats:italic>STXBP1<\/jats:italic>\n                      are a well\u2010established cause of developmental and epileptic encephalopathy (DEE), whereas their contribution to milder epilepsy phenotypes remains under\u2010characterized. We sought to delineate\n                      <jats:italic>STXBP1<\/jats:italic>\n                      variants across a clinical severity spectrum and to explore molecular correlates of phenotypic heterogeneity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Trio\u2010based whole\u2010exome sequencing was performed in patients with unexplained epilepsy recruited from multiple epilepsy centers. Variants were confirmed by Sanger sequencing and interpreted using ACMG criteria. Missense variants were assessed using structural modeling and biophysical prediction tools, and their effects on Munc18\u20101 expression were evaluated by immunoblotting in transfected HEK293T cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Eight\n                      <jats:italic>STXBP1<\/jats:italic>\n                      variants were identified in eight unrelated cases, including one truncating variant (Lys63Ter) and seven missense variants. Five\n                      <jats:italic>de novo<\/jats:italic>\n                      missense variants (Pro187Leu, Arg190Gln, Ala251Thr, Arg292His, and Gly544Val) and one\n                      <jats:italic>de novo<\/jats:italic>\n                      truncating variant were observed exclusively in individuals with DEE. In contrast, Gly236Val segregated in a family with epilepsy with febrile seizures plus, and Pro434Leu was inherited in a family with self\u2010limited epilepsy with centrotemporal spikes with incomplete penetrance.\n                      <jats:italic>In silico<\/jats:italic>\n                      analyses suggested that Gly236Val and Pro434Leu had comparatively milder destabilizing effects and were located at more solvent\u2010accessible positions than DEE\u2010associated variants. Consistently, immunoblotting showed markedly reduced Munc18\u20101 levels for DEE\u2010associated missense variants, whereas Gly236Val and Pro434Leu preserved similar Munc18\u20101 levels to wild\u2010type expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      <jats:italic>STXBP1<\/jats:italic>\n                      variants may underlie epilepsies of variable severity, extending from milder epilepsy syndromes to DEE. Clinical severity broadly tracks with the predicted structural\/biophysical impact of the variant and Munc18\u20101 abundance, providing a mechanistic clue for phenotypic heterogeneity in\n                      <jats:italic>STXBP1<\/jats:italic>\n                      \u2010related disorders.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.71093","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T06:50:55Z","timestamp":1787035855000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<i>STXBP1<\/i>\n                    Variants Associated With Epilepsy With Variable Severity"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2316-9373","authenticated-orcid":false,"given":"Meng","family":"Xu","sequence":"first","affiliation":[{"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  Guangzhou China"},{"name":"The Eighth Affiliated Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan)  Foshan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5476-8212","authenticated-orcid":false,"given":"Xuan","family":"Guo","sequence":"additional","affiliation":[{"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  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1596-6285","authenticated-orcid":false,"given":"Zhi\u2010kui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics\/Experimental Education\/Administration Center, School of Basic Medical Sciences Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1849-0100","authenticated-orcid":false,"given":"Yang","family":"Qi","sequence":"additional","affiliation":[{"name":"Genetic and Metabolic Center Laboratory Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region  Nanning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting\u2010ting","family":"Ye","sequence":"additional","affiliation":[{"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  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Xu","sequence":"additional","affiliation":[{"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  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei\u2010wen","family":"Deng","sequence":"additional","affiliation":[{"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  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min\u2010zhi","family":"Zhuang","sequence":"additional","affiliation":[{"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  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7962-8874","authenticated-orcid":false,"given":"Yi\u2010wu","family":"Shi","sequence":"additional","affiliation":[{"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  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2428-6165","authenticated-orcid":false,"given":"Fu","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics\/Experimental Education\/Administration Center, School of Basic Medical Sciences Southern Medical University  Guangzhou China"},{"name":"Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research &amp; Hainan Provincial Clinical The First Affiliated Hospital of Hainan Medical University, Hainan Medical University  Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7769-9564","authenticated-orcid":false,"given":"Xiao\u2010rong","family":"Liu","sequence":"additional","affiliation":[{"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  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"For the China Epilepsy Gene 1.0 Project","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1161748"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2020.05.036"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.806506"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002457"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2010.01575.x"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.15187"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz391"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1981.tb06159.x"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1989.tb05316.x"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2010.02522.x"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13709"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-017-0528-2"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2024.168494"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2020.626363"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz383"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-3011.1988.tb01261.x"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.18358"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.18539"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy046"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.287.5454.864"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2004.03503.x"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.150"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0387-7604(87)80110-9"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2010.02728.x"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2010.02767.x"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12439"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000291"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/ahg.12106"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2013.09.013"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1684\/epd.2013.0558"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2010.183"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37132"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20153621"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2016.04.005"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000200715"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab327"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10482-9"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2646"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000199"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4589"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12124"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/gbb.12456"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e11-02-0135"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.08.059"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3130"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000007089"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2023.06.005"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2020.559080"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.629610"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1997.tb01465.x"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.51.6.1608"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2017.02.012"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06507-4"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.304"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.00821"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2021.720984"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.632466"},{"issue":"11","key":"e_1_2_11_59_1","first-page":"2361","article-title":"Domain 3a of Munc18\u20101 Plays a Crucial Role at the Priming Stage of Exocytosis","volume":"126","author":"Han G. A.","year":"2013","journal-title":"Journal of Cell Science"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2022.11.002"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/35006120"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.514273"}],"container-title":["CNS Neuroscience &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cns.71093","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cns.71093","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cns.71093","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T07:00:52Z","timestamp":1787900452000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cns.71093"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":61,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/cns.71093"],"URL":"https:\/\/doi.org\/10.1002\/cns.71093","archive":["Portico"],"relation":{},"ISSN":["1755-5930","1755-5949"],"issn-type":[{"value":"1755-5930","type":"print"},{"value":"1755-5949","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8]]},"assertion":[{"value":"2025-10-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e71093"}}