{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T04:05:48Z","timestamp":1780459548079,"version":"3.54.1"},"reference-count":28,"publisher":"American Society for Clinical Investigation","issue":"2","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"vor","delay-in-days":52,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Australian National Health & Medical Research Council","award":["APP1185122,APP2019780"],"award-info":[{"award-number":["APP1185122,APP2019780"]}]},{"name":"National Institute of Neurological Disorders and Stroke of the National Institutes of Health","award":["U01HG007672"],"award-info":[{"award-number":["U01HG007672"]}]},{"DOI":"10.13039\/501100007734","name":"Stiftung Michael","doi-asserted-by":"crossref","award":["Canger-Janz-Fellowship"],"award-info":[{"award-number":["Canger-Janz-Fellowship"]}],"id":[{"id":"10.13039\/501100007734","id-type":"DOI","asserted-by":"crossref"}]},{"name":"DFG","award":["499552394 \u2013 SFB 1597,503306912 \u2013 FOR 5547,431984000 \u2013 SFB 1453"],"award-info":[{"award-number":["499552394 \u2013 SFB 1597,503306912 \u2013 FOR 5547,431984000 \u2013 SFB 1453"]}]},{"name":"Excellence Initiative Centre for Integrative Biological Signalling Studies","award":["(EXC-2189)(project ID 390939984)"],"award-info":[{"award-number":["(EXC-2189)(project ID 390939984)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,16]]},"abstract":"<jats:p>\n                    Disorders of\n                    <jats:italic>GABRA3<\/jats:italic>\n                    , the only epilepsy-associated GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptor subunit gene on the X chromosome, have eluded clinical clarity due to ambiguous inheritance patterns and variable phenotypes. The long-standing assumption that all pathogenic variants cause loss of function further obscured genotype\u2013phenotype relationships and hindered progress. Here, we curated a cohort of individuals with a\n                    <jats:italic>GABRA3<\/jats:italic>\n                    variant, integrating deep phenotyping, genotyping, family history, and electrophysiology with a targeted mouse model. Among 43 individuals with 19\n                    <jats:italic>GABRA3<\/jats:italic>\n                    variants, functional analyses revealed gain- and loss-of-function effects, each linked to distinct clinical profiles. Gain-of-function variants were associated with severe, treatment-resistant epilepsy and profound intellectual disability, disproportionately affecting males, who were often nonambulant and had cortical visual impairment. Loss-of-function variants produced milder phenotypes, with epilepsy rarely observed; affected males showed behavioral issues and language delay, while females were unaffected carriers. Our gain-of-function (\n                    <jats:italic>Gabra3<\/jats:italic>\n                    <jats:sup>Q242L\/+<\/jats:sup>\n                    ) mouse model mirrored these sex-specific differences, showing increased seizure susceptibility, early death, and marked cortical hyperexcitability. These insights resolve longstanding uncertainties surrounding\n                    <jats:italic>GABRA3<\/jats:italic>\n                    and redefine how X-linked disorders are interpreted. They demonstrate that it is the functional impact of a variant, not its mere presence, that determines whether a condition manifests dominantly or recessively. This distinction carries important implications for genetic counseling, precision medicine, and the broader interpretation of X-linked neurodevelopmental disorders.\n                  <\/jats:p>","DOI":"10.1172\/jci189830","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T17:01:16Z","timestamp":1764090076000},"source":"Crossref","is-referenced-by-count":2,"title":["Functional consequence of pathogenic GABRA3 variants determines whether X-linked inheritance is dominant or recessive"],"prefix":"10.1172","volume":"136","author":[{"given":"Katrine M.","family":"Johannesen","sequence":"first","affiliation":[{"name":"Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark."},{"name":"Department of Genetics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khaing Phyu","family":"Aung","sequence":"additional","affiliation":[{"name":"The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian W.Y.","family":"Liao","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Camperdown, New South Wales, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Absalom","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Camperdown, New South Wales, Australia."},{"name":"School of Science, The MARCS Institute for Brain, Behaviour and Development, University of Western Sydney, Sydney, New South Wales, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han C.","family":"Chua","sequence":"additional","affiliation":[{"name":"Sydney Pharmacy School, Faculty of Medicine and Health and Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue N.","family":"Gan","sequence":"additional","affiliation":[{"name":"The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaomiao","family":"Mao","sequence":"additional","affiliation":[{"name":"The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaseley E.","family":"McKenzie","sequence":"additional","affiliation":[{"name":"The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hian M.","family":"Lee","sequence":"additional","affiliation":[{"name":"The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Ortiz","sequence":"additional","affiliation":[{"name":"Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark."},{"name":"Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca C.","family":"Spillmann","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vandana","family":"Shashi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodney A.","family":"Radtke","sequence":"additional","affiliation":[{"name":"Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2648-7657","authenticated-orcid":true,"given":"Ghayda M.","family":"Mirzaa","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology and"},{"name":"Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA."},{"name":"Brotman Baty Institute for Precision Medicine, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. Anne","family":"Weisner","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josue","family":"Flores Daboub","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Genetics Division, University of Utah School of Medicine, Salt Lake City, Utah, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Hagedorn","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Genetics Division, University of Utah School of Medicine, Salt Lake City, Utah, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3241-6273","authenticated-orcid":true,"given":"Pinar","family":"Bayrak-Toydemir","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Utah, Salt Lake City, Utah, USA."},{"name":"ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desiree","family":"DeMille","sequence":"additional","affiliation":[{"name":"ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Utah, Salt Lake City, Utah, USA."},{"name":"ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nandita","family":"Bajaj","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, Christian Children\u2019s Hospital Osnabr\u00fcck, Osnabr\u00fcck, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yline","family":"Capri","sequence":"additional","affiliation":[{"name":"Department of Genetics, Robert Debr\u00e9 Hospital, Assistance Publique\u2013H\u00f4pitaux de Paris Nord, University of Paris, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6172-8247","authenticated-orcid":true,"given":"Boris","family":"Keren","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Assistance Publique\u2013H\u00f4pitaux de Paris, Sorbonne Universit\u00e9, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1714-6749","authenticated-orcid":true,"given":"Miriam","family":"Schmidts","sequence":"additional","affiliation":[{"name":"Center for Pediatrics and Adolescent Medicine, Freiburg University Hospital, Faculty of Medicine, and"},{"name":"CIBSS \u2013 Centre for Integrative Biological Signaling Studies, University of Freiburg, Freiburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid M.B.H.","family":"van de Laar","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjon A.","family":"van Slegtenhorst","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafal","family":"Ploski","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Warsaw Medical University, Warsaw, Poland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Bogotko","sequence":"additional","affiliation":[{"name":"Professor Jan Bogdanowicz Children\u2019s Hospital, Warsaw, Poland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle 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C.","family":"Win","sequence":"additional","affiliation":[{"name":"Department of Neurology, Riley Children\u2019s Health, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilo","family":"Espinosa-Jovel","sequence":"additional","affiliation":[{"name":"Epilepsy Program, Instituto Roosevelt, Bogot\u00e1, Colombia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia","family":"Zacher","sequence":"additional","affiliation":[{"name":"Center for Adults with Disability (MZEB), Epilepsy Center Kleinwachau, Radeberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konrad","family":"Platzer","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel 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A.","family":"Reid","sequence":"additional","affiliation":[{"name":"The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip K.","family":"Ahring","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Camperdown, New South Wales, 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