Early onset or syndromic epilepsy

Gene: GABRA3

Green List (high evidence)

Comment on list classification: There are numerous patients reported in literature with variants in GABRA3 and epilepsy. GOF variants cause a more severe, X-linked dominant phenotype (early-onset, treatment resistant epilepsy), while LOF variants usually result in a milder phenotype (epilepsy is rare) and an X-linked recessive inheritance pattern. Functional evidence in mouse models supports these mechanistic findings. Based on available evidence, GABRA3 should be promoted to Green with MOI X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males).

Created: 10 Mar 2026, 5:10 p.m. | Last Modified: 10 Mar 2026, 5:17 p.m.

Panel Version: 8.133

PMID: 41289009 Johannesen et al., 2025
Cohort of 43 individuals (18 males and 25 females) with GABRA3 variants - some reported previously. Detailed genotype–phenotype analyses showed that pathogenic GABRA3 variants can cause either dominant or recessive X-linked disorders. GOF variants caused severe phenotypes and followed X-linked dominant inheritance, while LOF variants resulted in milder phenotypes and followed an X-linked recessive pattern. 30 individuals are described in detail, others excluded due to family history or neutral impact of variant.

Among the 20 individuals with GOF variants, 85% (17/20) had epilepsy with a median age of onset at 33 months (range 2–252 months). In contrast, only 10% (1/10) with LOF variants had epilepsy, with onset at 4 months. Individuals with GOF variants were more likely to have severe ID (8/20 vs. 0/10 in LOF group). Female carriers of LOF variants were unaffected.

Functional evidence from PMID: 41289009 - Gabra3 KO mice do not exhibit early mortality or seizures; in contrast, an engineered mouse model carrying the GOF p.(Gln242Leu) variant recapitulated key human findings: male pups were not viable, while female mice had increased mortality in the first 2 months of life, and developed seizures in adulthood.

GABRA3 is linked to Epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features, OMIM:301091 (OMIM accessed 10th Mar 2026).
Sources: Literature

Created: 10 Mar 2026, 5:07 p.m. | Last Modified: 10 Mar 2026, 5:16 p.m.

Panel Version: 8.133

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features, OMIM:301091

Publications

• 41289009