RBFOX3

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0005027

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0005027

Submitter: ClinGen

*RBFOX3* was first reported in relation to autosomal dominant epilepsy in 2013 with the description of three affected individuals from two families (family 1 and family 4) in a single paper (Lal D et al., PMID: 24039908), which remains the sole *RBFOX3* gene-disease relationship report to date. Family 1 includes one female with nocturnal generalized tonic clonic seizures and a sibling with centrotemporal spikes but no seizures. Both siblings were found to have a 365 kb deletion involving RBFOX1; the individual with nocturnal generalized tonic clonic seizures was also found to have a 3.43 kb deletion of RBFOX3. Parental testing was not performed. Genomic coordinates for the *RBFOX3* deletion were not provided in the paper; because we do not know the true boundaries or the extent of the genomic content in the deletion, we decided not to score the variant. Family 4 includes one individual with nocturnal generalized tonic clonic seizures and a sibling with epileptic encephalopathy with status epilepticus during sleep. Both of these individuals were found to have a nonsense variant in RBFOX3; of note, this variant was also identified in their unaffected father. Because this variant was found in proband’s unaffected father and the presentation of the siblings was disparate, we decided not to score the variant. Although neither the deletion or nonsense variant is present in gnomAD v4.1.1, several additional stop/gain variants are present at high frequencies in the general population suggesting that this gene may be tolerant of loss of function variation. Two animal model studies were reviewed during this curation which drew a possible link between *RBFOX3* and autosomal dominant epilepsy (PMIDs: 26619789 and 35951651). However, these studies focused on homozygous knockout mice where complete loss of gene function was studied. To date, all reported patients with *RBFOX3* mutations carry heterozygous variants, therefore we did not score these animal models. In summary, the evidence supporting the relationship between *RBFOX3* and autosomal dominant epilepsy has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *RBFOX3* plays in this disease. This classification was approved by the ClinGen Epilepsy GCEP on November 19th, 2024 (SOP v.11).