Functional consequence of pathogenic GABRA3 variants determines whether X-linked inheritance is dominant or recessive

Disorders of GABRA3, the only epilepsy-associated GABAA 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-phenotype relationships and hindered progress. Here, we curated a cohort of individuals with a GABRA3 variant, integrating deep phenotyping, genotyping, family history, and electrophysiology with a targeted mouse model. Among 43 individuals with 19 GABRA3 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 (Gabra3Q242L/+) mouse model mirrored these sex-specific differences, showing increased seizure susceptibility, early death, and marked cortical hyperexcitability. These insights resolve longstanding uncertainties surrounding GABRA3 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.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-11-25
DOI
https://doi.org/10.1172/jci189830
Citations
1
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
1.82

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article

Functional consequence of pathogenic GABRA3 variants determines whether X-linked inheritance is dominant or recessive

Miaomiao Mao, Lauren Chad, Boris Keren, Jian Zhao et al.
1 citations
Journal of Clinical Investigation
Genomics and Rare Diseases
1.82
article

Functional consequence of pathogenic GABRA3 variants determines whether X-linked inheritance is dominant or recessive

Miaomiao Mao, Lauren Chad, Boris Keren, Jian Zhao, Carolina I. Galaz-Montoya, Ebba Alkhunaizi, Katrine M. Johannesen, Josue Flores Daboub, Guido Rubboli, Joe Win, Pia Zacher, Chaseley E. McKenzie, Vivian W. Y. Liao, Ingrid M. Wentzensen, Katie Angione, Yline Capri, Danielle K. Bourque, Houda Zghal Elloumi, Miriam Schmidts, Viorelia Rusu, Rafał Płoski, Ingrid Eileen Scheffer, Michael C. Kruer, Hian M. Lee, Han Chow Chua, Xuetao Gan, Nathan L. Absalom, Sebastian Ortiz, Samuel F. Berkovic, Dominique Braun, Khaing Phyu Aung, Nada Quercia, Nandita Bajaj, Christopher M. Reid, Patricia A. Weisner, Konrad Platzer, Philip K. Ahring, Marjon A. van Slegtenhorst, Rikke S. Møller, Mary Chebib, Ingrid M.B.H. van de Laar, Desiree DeMille, Vandana Shashi, Ghayda Mirzaa, Rodney A. Radtke, Pritha Bisarad, Pinar Bayrak‐Toydemir, Caroline Hagedorn, Rebecca C. Spillmann, Marta Bogotko, Camilo Espinosa-Jovel
article en
1 citations

Abstract

Disorders of GABRA3, the only epilepsy-associated GABAA 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-phenotype relationships and hindered progress. Here, we curated a cohort of individuals with a GABRA3 variant, integrating deep phenotyping, genotyping, family history, and electrophysiology with a targeted mouse model. Among 43 individuals with 19 GABRA3 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 (Gabra3Q242L/+) mouse model mirrored these sex-specific differences, showing increased seizure susceptibility, early death, and marked cortical hyperexcitability. These insights resolve longstanding uncertainties surrounding GABRA3 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.

Journal of Clinical InvestigationVol. 136(2)
GenVec (US), University of Bern (CH), University of Copenhagen (DK), The University of Sydney (AU), Royal Children's Hospital (AU), Barrow Neurological Institute (US), University of Indianapolis (US), University of Arizona (US), University of Freiburg (DE), The University of Melbourne (AU), Duke University (US), University of Southern Denmark (DK), University of Toronto (CA), University of Washington (US), University of Utah (US), Florey Institute of Neuroscience and Mental Health (AU), Medical University of Warsaw (PL), Children's Hospital of Eastern Ontario (CA), University Hospital of Bern (CH), University Medical Center Freiburg (DE), Hospital for Sick Children (CA), Erasmus MC (NL), Rigshospitalet (DK), Riley Hospital for Children (US), Sorbonne Université (FR), ARUP Laboratories (United States) (US), Uniwersytecki Szpital Dziecięcy (PL), Instituto Neurológico de Colombia (CO), Newborn Screening Ontario (CA), Children's Hospital Colorado (US), Assistance Publique – Hôpitaux de Paris (FR), Pitié-Salpêtrière Hospital (FR), Phoenix Children's Hospital (US), Hôpital Robert-Debré (FR), Brotman Baty Institute (US), Klinikum Osnabrück (DE), SickKids Foundation (CA), Epilepsy Action (GB), Interdisciplinary University of Paris (FR), Filadelfia (DK), Pediatrics and Genetics (US), Epilepsiezentrum Kleinwachau Gemeinnützige (DE), Austin Health (AU), ARUP Institute for Clinical and Experimental Pathology, Université Paris 1 Panthéon-Sorbonne (FR), Indiana University – Purdue University Indianapolis (US), Seattle University (US), ARUP Laboratories (United States) (US), Western Sydney University (AU), University of Colorado Denver (US), Leipzig University (DE)
Lundbeckfonden, Stiftung Michael, H. Lundbeck A/S, National Institutes of Health, Medical Research Council, National Health and Medical Research Council
Openalex Percentile: Top 11%
Genomics and Rare Diseases
1.82
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