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

Authors:
Open Access
Publisher website
Google Scholar
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, 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 ( Gabra3 Q242L/+ ) 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.
Funding Information
  • Australian National Health & Medical Research Council (APP1185122, APP2019780)
  • National Institute of Neurological Disorders and Stroke of the National Institutes of Health (U01HG007672)
  • Stiftung Michael (Canger-Janz-Fellowship)
  • DFG (499552394 – SFB 1597, 503306912 – FOR 5547, 431984000 – SFB 1453)
  • Excellence Initiative Centre for Integrative Biological Signalling Studies ((EXC-2189)(project ID 390939984))

This publication has 29 references indexed in Scilit: