NM_194248.3(OTOF):c.4799+1G>T

For OTOF c.4799+1G>T, otoferlin gene augmentation remains the strongest mechanism-matched therapeutic direction because this canonical splice-donor variant is expected to produce severe loss of normal otoferlin function, and current OTOF programs bypass the endogenous splice defect by restoring a functional coding sequence.

ClinVar classifies OTOF c.4799+1G>T as pathogenic. Preclinical dual-AAV studies restored otoferlin expression and improved auditory phenotypes in DFNB9 mouse models (PMID:30782832; PMID:30509897). Early human clinical data have shown hearing restoration signals after OTOF cochlear gene transfer in children, including AAV1-hOTOF experience (PMID:38280389), with additional studies ongoing (NCT:NCT05788536; NCT:NCT05821959). Because c.4799+1G>T is a canonical splice-site loss-of-function allele in a biallelic recessive condition, replacement is more directly supported than variant-specific splice repair at the current stage of development.

The available human evidence remains early-phase and disease-level rather than specific to c.4799+1G>T. Real-world interpretation still depends on confirming biallelic OTOF-mediated disease, cochlear target-cell viability, surgical timing, and durability. The optimal age window and re-dosing constraints remain unresolved.