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Targeted sequencing of 41 HSP-associated genes in 74 patients from 71 families included USP8 among the candidates. A single novel likely pathogenic USP8 variant was detected in one proband and segregated with disease in one additional affected relative (PMID:40445718); no other USP8 variants were reported in this cohort. This yields only minimal case-level support for USP8 involvement in hereditary spastic paraplegia.
To date, there are no functional or mechanistic data demonstrating a role for USP8 in corticospinal tract integrity or axonal maintenance in HSP models. The absence of replication in unrelated families and lack of experimental concordance limit the clinical validity of USP8 as a monogenic cause of HSP.
Gene–Disease AssociationLimitedSingle proband with USP8 variant, segregation in one relative, no replication Genetic EvidenceLimitedOnly one likely pathogenic USP8 variant identified among 71 families; no additional cases Functional EvidenceLimitedNo functional or mechanistic studies of USP8 in HSP models |