OTOF gene-augmentation rationale for c.5013G>A (p.Trp1671Ter)

For OTOF c.5013G>A (p.Trp1671Ter), otoferlin gene augmentation remains the strongest mechanism-matched therapeutic direction because this nonsense variant is expected to abolish normal protein function in a recessive loss-of-function disease, and current OTOF programs aim to restore a working otoferlin coding sequence rather than repair the specific codon.

ClinVar classifies OTOF c.5013G>A (p.Trp1671Ter) as pathogenic. Dual-AAV preclinical studies restored otoferlin expression and improved hearing-related phenotypes in DFNB9 mouse models (PMID:30782832; PMID:30509897). Early human clinical data now support translational feasibility: pediatric OTOF gene-transfer studies have reported hearing restoration signals after cochlear delivery, including AAV1-hOTOF experience (PMID:38280389), with additional trials ongoing (NCT:NCT05788536; NCT:NCT05821959). Because p.Trp1671Ter is a true stop-gain allele in a gene where haploinsufficiency is not the main issue but biallelic loss is, replacement is more directly justified than speculative codon-specific editing.

The available human evidence remains early-phase and disease-level rather than specific to p.Trp1671Ter. Real clinical interpretation still depends on confirming biallelic OTOF-mediated deafness, cochlear target-cell viability, surgical access, and follow-up durability. The optimal treatment window in children and the constraints on re-dosing remain unresolved.