{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:01:32Z","timestamp":1791928892490,"version":"4.3.4"},"reference-count":38,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T00:00:00Z","timestamp":1764979200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T00:00:00Z","timestamp":1764979200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003554","name":"Lundbeck Foundation","doi-asserted-by":"publisher","award":["R383\u20102022\u2010276"],"award-info":[{"award-number":["R383\u20102022\u2010276"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Variants in\n                      <jats:italic>GABRG2<\/jats:italic>\n                      , encoding the \u03b32 subunit of the \u03b3\u2010aminobutyric acid type A receptor, are linked to epilepsy phenotypes of varying severity, with gain\u2010of\u2010function (GoF) variants associated with the more severe phenotypes than loss\u2010of\u2010function variants. Here, we provide a comprehensive analysis of the early clinical features, motor, language, and eating abilities, and structural consequences of the recurrent\n                      <jats:italic>GABRG2<\/jats:italic>\n                      p.(Ala106Thr) GoF variant, aiming to refine genotype\u2013phenotype correlations and deepen the understanding of GoF\u2010associated\n                      <jats:italic>GABRG2<\/jats:italic>\n                      disorders.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Individuals were recruited through international collaborations, literature review, and patient advocacy groups. Clinical data were collected via standardized interviews and physician reports. Functional effects were assessed using electrophysiological recordings. Structural modeling was performed using homology\u2010based approaches to evaluate conformational changes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We collected 23 unrelated individuals harboring the\n                      <jats:italic>GABRG2<\/jats:italic>\n                      p.(Ala106Thr) variant. Symptoms began with early dysphagia (median onset age\u2009=\u20091\u2009month), hypotonia, seizures (median onset age\u2009=\u20092\u2009months), and hyperkinetic movement disorders (median onset age\u2009=\u20093\u2009months). Epilepsy was present in 91% of the individuals, 71% featuring a developmental and epileptic encephalopathy; 33% of the individuals with epilepsy achieved seizure freedom during the follow\u2010up. All individuals exhibited moderate to severe cognitive\/neurodevelopmental impairment, with profound deficits in motor, language, and other domains. Functional analysis confirmed a GoF effect of the p.(Ala106Thr) variant. By contrast, another variant affecting the same residue, p.(Ala106Pro), which is observed in population databases, was functionally characterized as neutral. Structural modeling indicated that the p.(Ala106Thr) variant may enhance receptor gating by facilitating a hydrogen bond between the extracellular and transmembrane domains, a mechanism not observed with the p.(Ala106Pro) variant.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>\n                      Although some individuals exhibited severe developmental impairment without epilepsy, our findings demonstrate that the recurrent\n                      <jats:italic>GABRG2<\/jats:italic>\n                      p.(Ala106Thr) GoF variant is consistently associated with a severe neurodevelopmental phenotype. Despite its profound clinical impact, in silico tools consistently predict this variant as benign, highlighting a critical gap in current predictive models.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.70045","type":"journal-article","created":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T10:58:06Z","timestamp":1765018686000},"page":"1371-1385","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Early neurological symptoms and epilepsy outcomes in individuals with the recurrent\n                    <scp>\n                      <i>GABRG2<\/i>\n                    <\/scp>\n                    p.(\n                    <scp>Ala106Thr<\/scp>\n                    ) gain\u2010of\u2010function variant: Structural and phenotypic insights"],"prefix":"10.1111","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3432-1932","authenticated-orcid":false,"given":"Sebastian","family":"Ortiz","sequence":"first","affiliation":[{"name":"Department of Epilepsy Genetics and Personalized Medicine Danish Epilepsy Center, member of European Reference Network EpiCARE  Dianalund Denmark"},{"name":"Department of Regional Health Research, Faculty of Health Sciences University of Southern Denmark  Odense Denmark"},{"name":"Instituto Roosevelt  Bogot\u00e1 Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6782-8912","authenticated-orcid":false,"given":"Chiara","family":"Bagliani","sequence":"additional","affiliation":[{"name":"Department of Epilepsy Genetics and Personalized Medicine Danish Epilepsy Center, member of European Reference Network EpiCARE  Dianalund Denmark"},{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health University of Genoa  Genoa Italy"},{"name":"Child Neuropsychiatry Unit IRCCS Istituto Giannina Gaslini, member of European Reference Network EpiCARE  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3587-0957","authenticated-orcid":false,"given":"Susan X. N.","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neuroscience University of Copenhagen  Copenhagen Denmark"},{"name":"Brain and Mind Centre, School of Medical Sciences, Faculty of Medicine and Health University of Sydney  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9123-9057","authenticated-orcid":false,"given":"Ali S.","family":"Kusay","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences Link\u00f6ping University  Link\u00f6ping Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8456-0029","authenticated-orcid":false,"given":"Katri","family":"Silvennoinen","sequence":"additional","affiliation":[{"name":"Kuopio Epilepsy Center, Neurology, Neurocenter Kuopio University Hospital, member of European Reference Network EpiCARE  Kuopio Finland"},{"name":"Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences University of Eastern Finland  Kuopio Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2935-5131","authenticated-orcid":false,"given":"Reetta","family":"K\u00e4lvi\u00e4inen","sequence":"additional","affiliation":[{"name":"Kuopio Epilepsy Center, Neurology, Neurocenter Kuopio University Hospital, member of European Reference Network EpiCARE  Kuopio Finland"},{"name":"Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences University of Eastern Finland  Kuopio Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9600-4406","authenticated-orcid":false,"given":"Leena","family":"Jutila","sequence":"additional","affiliation":[{"name":"Kuopio Epilepsy Center, Neurology, Neurocenter Kuopio University Hospital, member of European Reference Network EpiCARE  Kuopio Finland"},{"name":"Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences University of Eastern Finland  Kuopio Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8582-2369","authenticated-orcid":false,"given":"Anni","family":"Saarela","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences University of Eastern Finland  Kuopio Finland"},{"name":"Kuopio Epilepsy Center, Pediatric Neurology Kuopio University Hospital, member of European Reference Network EpiCARE  Kuopio Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2672-287X","authenticated-orcid":false,"given":"Rebekka S.","family":"Dahl","sequence":"additional","affiliation":[{"name":"Department of Epilepsy Genetics and Personalized Medicine Danish Epilepsy Center, member of European Reference Network EpiCARE  Dianalund Denmark"},{"name":"Department of Regional Health Research, Faculty of Health Sciences University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1242-5260","authenticated-orcid":false,"given":"Tommy","family":"St\u00f6dberg","sequence":"additional","affiliation":[{"name":"Department of Child Neurology Karolinska University Hospital  Stockholm Sweden"},{"name":"Department of Women's and Children's Health Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9212-2691","authenticated-orcid":false,"given":"Carla","family":"Marini","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatric Unit, Pediatric Hospital G. 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