{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T11:07:07Z","timestamp":1789816027919,"version":"4.0.1"},"reference-count":37,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,12,21]],"date-time":"2024-12-21T00:00:00Z","timestamp":1734739200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS119977"],"award-info":[{"award-number":["R01 NS119977"]}],"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":["U54 NS108874"],"award-info":[{"award-number":["U54 NS108874"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      <jats:italic>SCN2A<\/jats:italic>\n                      encodes the voltage\u2010gated sodium (Na+) channel \u03b1 subunit Na\n                      <jats:sub>V<\/jats:sub>\n                      1.2, which is important for the generation and forward and back propagation of action potentials in neurons. Genetic variants in\n                      <jats:italic>SCN2A<\/jats:italic>\n                      are associated with a spectrum of neurodevelopmental disorders. However, the mechanisms whereby variation in\n                      <jats:italic>SCN2A<\/jats:italic>\n                      leads to disease remains incompletely understood, and the full spectrum of\n                      <jats:italic>SCN2A<\/jats:italic>\n                      \u2010related disorders may not be fully delineated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Here, we identified seven de novo heterozygous variants in\n                      <jats:italic>SCN2A<\/jats:italic>\n                      in eight individuals with developmental and epileptic encephalopathy (DEE) accompanied by prominent malformation of cortical development (MCD). We characterized the electrophysiological properties of Na\u2009+\u2009currents in human embryonic kidney (HEK) cells transfected with the adult (A) or neonatal (N) isoform of wild\u2010type (WT) and variant Na\n                      <jats:sub>V<\/jats:sub>\n                      1.2 using manual and automated whole\u2010cell voltage clamp recording.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The neonatal isoforms of all\n                      <jats:italic>SCN2A<\/jats:italic>\n                      variants studied exhibit gain of function (GoF) with a large depolarized shift in steady\u2010state inactivation, creating a markedly enhanced window current common across all four variants tested. Computational modeling demonstrated that expression of the Na\n                      <jats:sub>V<\/jats:sub>\n                      1.2\u2010p.Met1770Leu\u2010N variant in a developing neocortical pyramidal neuron results in hyperexcitability.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>\n                      These results support expansion of the clinical spectrum of\n                      <jats:italic>SCN2A<\/jats:italic>\n                      \u2010related disorders and the association of genetic variation in\n                      <jats:italic>SCN2A<\/jats:italic>\n                      with MCD, which suggests previously undescribed roles for\n                      <jats:italic>SCN2A<\/jats:italic>\n                      in fetal brain development.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.18234","type":"journal-article","created":{"date-parts":[[2024,12,21]],"date-time":"2024-12-21T08:30:11Z","timestamp":1734769811000},"page":"914-928","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Rare dysfunctional\n                    <scp>\n                      <i>SCN2A<\/i>\n                    <\/scp>\n                    variants are associated with malformation of cortical development"],"prefix":"10.1111","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2896-3469","authenticated-orcid":false,"given":"J\u00e9r\u00f4me","family":"Clatot","sequence":"first","affiliation":[{"name":"Division of Neurology, Department of Pediatrics The Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"The Epilepsy Neurogenetics Initiative The Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher H.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Sotardi","sequence":"additional","affiliation":[{"name":"Department of Radiology The Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2065-9211","authenticated-orcid":false,"given":"Jinan","family":"Jiang","sequence":"additional","affiliation":[{"name":"The University of California  Berkeley California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Trivisano","sequence":"additional","affiliation":[{"name":"Child Neurology, Epilepsy and Movement Disorders, Bambino Ges\u00f9 IRCCS Children's Hospital  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Balestrini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Medical Genetics Meyer Children's Hospital IRCCS  Florence Italy"},{"name":"University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Isum","family":"Ward","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of South Dakota Sanford School of Medicine  Sioux Falls South Dakota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Ginn","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Pediatrics The Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"The Epilepsy Neurogenetics Initiative The Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brunetta","family":"Guaragni","sequence":"additional","affiliation":[{"name":"Neonatology and Neonatal Intensive Care Unit Children's Hospital, ASST\u2010Spedali Civili of Brescia  Brescia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Malerba","sequence":"additional","affiliation":[{"name":"Unit of Child Neurology and Psychiatry ASST\u2010Spedali Civili of Brescia  Brescia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4363-468X","authenticated-orcid":false,"given":"Angeliki","family":"Vakrinou","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy UCL Queen Square Institute of Neurology  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mia","family":"Sherer","sequence":"additional","affiliation":[{"name":"Department of Neurology The University of California  Sacramento California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo","family":"Helbig","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Pediatrics The Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"The Epilepsy Neurogenetics Initiative The Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Department of Neurology The University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"},{"name":"Department of Biomedical and Health Informatics (DBHi) Children's Hospital of Philadelphia  Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ala","family":"Somarowthu","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Pediatrics The Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1511-5893","authenticated-orcid":false,"given":"Sanjay M.","family":"Sisodiya","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy UCL Queen Square Institute of Neurology  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy","family":"Ben\u2010Shalom","sequence":"additional","affiliation":[{"name":"Department of Neuroscience The University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renzo","family":"Guerrini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Medical Genetics Meyer Children's Hospital IRCCS  Florence Italy"},{"name":"University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8120-0287","authenticated-orcid":false,"given":"Nicola","family":"Specchio","sequence":"additional","affiliation":[{"name":"Child Neurology, Epilepsy and Movement Disorders, Bambino Ges\u00f9 IRCCS Children's Hospital  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3993-966X","authenticated-orcid":false,"suffix":"Jr","given":"Alfred L.","family":"George","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7404-735X","authenticated-orcid":false,"given":"Ethan M.","family":"Goldberg","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Pediatrics The Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"The Epilepsy Neurogenetics Initiative The Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Department of Biomedical and Health Informatics (DBHi) Children's Hospital of Philadelphia  Pennsylvania USA"},{"name":"Department of Neuroscience The University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,12,21]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-020-00418-4"},{"issue":"3","key":"e_1_2_11_3_1","first-page":"S59","article-title":"Phenotypic spectrum and genetics of SCN2A\u2010related disorders, treatment options, and outcomes in epilepsy and beyond","volume":"60","author":"Wolff M","year":"2019","journal-title":"Epilepsia"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.202313375"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae125"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.07.052"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25809"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25188"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2019.12.004"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aws019"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awu082"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx358"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2016-104509"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2017.01.014"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.16854"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12041-019-1104-3"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2023.2363"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2892"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.braindev.2019.09.004"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy326"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.14074"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.148"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-022-03454-1"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19057"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2017.01.009"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2012.02.024"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.3389\/fninf.2016.00017"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201912442"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddac087"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109483"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.05.037"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.3389\/fninf.2022.884046"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncir.2015.00044"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-021-00949-0"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0310-17.2017"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2018.03.011"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.51105"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.18234","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T11:44:08Z","timestamp":1764416648000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/epi.18234"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,21]]},"references-count":37,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,3]]}},"alternative-id":["10.1111\/epi.18234"],"URL":"https:\/\/doi.org\/10.1111\/epi.18234","archive":["Portico"],"relation":{},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,21]]},"assertion":[{"value":"2024-05-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}