USP25

Inheritance Pattern: AD

Disease ID:MONDO:0976128

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0005027

Submitter: ClinGen

*USP25* was first reported in relation to autosomal dominant epilepsy in 2024 in a single paper (Fan 2024, PMID: 38875478) describing 5 probands with variants in this gene and various types of seizures, intellectual disability and normal brain MRIs. The reported variants included one nonsense, one 3-base pair deletion, and three missense variants; 3 of these variants were inherited from a parent with seizure history (PMID: 38875478). Per gnomAD v4.1, *USP25* is not constrained for either missense or loss of function variation, and none of the variants reported in Fan et al. had any convincing supportive functional information. Some of the reported variants were also present in gnomAD. Because of this, the case-level data was not considered strong enough to score. *USP25* encodes a deubiquitinating enzyme that is involved in protein degradation. The functional impact of these variants on the ubiquitination pathway was examined in HEK293T cells and was not consistent. In addition, the significance of these functional studies in relationship to seizures was difficult to interpret. Functional studies of the nonsense variant showed that the truncated protein was produced, stable, and showed a possible dominant-negative or gain-of-function effect. In addition, a knock-out mouse model was generated but did not exhibit spontaneous seizures, which was not considered an appropriate model by this GCEP and therefore was not scored. Also, the study focused on homozygous knock-out mice whereas all reported individuals carried heterozygous variants. The homozygous knock-out model did show a higher propensity for seizures when induced compared to wild-type; however, this loss-of-function model did not fit with the possible dominant-negative or gain-of-function disease mechanism postulated for the nonsense variant. In summary, the evidence supporting the relationship between *USP25* 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 *USP25* plays in epilepsy. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on April 1, 2025 (SOP version 11).