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

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, dispro

SUBMITTER: Johannesen KM 

PROVIDER: S-EPMC12807467 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature