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Epilepsy is a heterogeneous disorder characterized by recurrent seizures. The neuronal splicing factor RBFOX1 (HGNC:18222) has emerged as a candidate risk gene due to structural and sequence variants that disrupt its function in affected individuals. Evidence includes familial cases of focal onset seizures co-segregating with RBFOX1 exon deletions and de novo translocations disrupting the A2BP1 locus, as well as microdeletions and sequence variants in rolandic epilepsy cohorts. Altered RBFOX1 dosage is hypothesised to perturb alternative splicing networks critical for neuronal excitability.
Genetic studies report two affected siblings with focal seizures carrying a heterozygous RBFOX1 exon1–2 deletion in combination with a CHRNB2 variant, inherited in an autosomal dominant pattern with variable expressivity (PMID:37033539). Two de novo translocations disrupting RBFOX1 were identified in individual patients with epilepsy, indicating direct gene disruption in unrelated cases (PMID:15148587). High-density SNP array screening of 289 unrelated rolandic epilepsy patients revealed hemizygous RBFOX1 deletions and novel exonic sequence variants, including a frameshift p.Ala233ValfsTer74, segregating with the electroencephalographic trait in families (PMID:24039908).
The inheritance mode is autosomal dominant with variable penetrance. Segregation evidence is limited by co-occurrence of CHRNB2 variants in the family report, and no additional affected relatives with isolated RBFOX1 disruptions have been documented. Recurrent hemizygous deletions of RBFOX1 5′ exons in rolandic epilepsy patients support a dosage-sensitive mechanism. No population-specific founder alleles have been described.
Functional data demonstrate that RBFOX1 binds UGCAUG elements to regulate neuron-specific alternative splicing programs. Although these assays confirm RBFOX1’s role in splicing regulation of transcripts implicated in neuronal excitability, no epilepsy-specific functional model has yet been reported, leaving mechanistic links to seizure phenotypes to be fully elucidated.
No studies to date have refuted the association; however, the contribution of co-segregating CHRNB2 variants in familial cases introduces complexity. The convergence of independent RBFOX1 disruptions in multiple unrelated epilepsy cases and consistent functional impact on neuronal splicing supports a dosage-dependent haploinsufficiency model.
In summary, heterozygous RBFOX1 disruptions—through exon deletions, translocations, and frameshift mutations—are associated with epilepsy risk. While additional large-scale case–control and functional in vivo studies are needed, current evidence is sufficient to warrant clinical consideration of RBFOX1 testing in unexplained familial epilepsy, particularly in focal seizure syndromes.
Gene–Disease AssociationModerateFour unrelated probands including two familial cases and de novo disruptions across distinct cohorts with segregation and dosage disruption evidence Genetic EvidenceModerateHeterozygous RBFOX1 exon deletions in two siblings and de novo translocations in two patients; hemizygous deletions and a frameshift variant in 289 rolandic epilepsy cases Functional EvidenceLimitedIn vitro assays confirm RBFOX1 binds UGCAUG to regulate neuronal splicing, but no epilepsy-specific functional model reported |