J Clin Invest. 2025 Nov 25:e189830. doi: 10.1172/JCI189830. Online ahead of print.
ABSTRACT
Disorders of GABRA3, the only epilepsy-associated GABA-A 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, electrophysiology, with a targeted mouse model. Among 43 individuals with 19 GABRA3 variants, functional analyses revealed both gain- and loss-of-function effects, each linked to distinct clinical profiles. Gain-of-function variants were associated with severe, treatment-resistant epilepsy and severe-profound intellectual disability, disproportionately affecting males, who were often non-ambulant and had cortical visual impairment. Loss-of-function variants produced milder phenotypes, with epilepsy rarely observed; affected males showed behavioural 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 not only resolve longstanding uncertainties surrounding GABRA3 but also 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 counselling, precision medicine, and the broader interpretation of X-linked neurodevelopmental disorders.
PMID:41289009 | DOI:10.1172/JCI189830
