OTOF augmentation rationale for c.3679C>T (p.Arg1227Ter)

For OTOF c.3679C>T (p.Arg1227Ter), otoferlin gene augmentation is the most direct currently actionable strategy because this early stop-gain allele likely eliminates otoferlin expression, and existing clinical programs are designed to replace the entire coding sequence rather than repair sporadic transcripts.

ClinVar classifies OTOF c.3679C>T (p.Arg1227Ter) as pathogenic. Dual-AAV preclinical studies restored otoferlin expression and recovered auditory phenotypes in DFNB9 mouse models (PMID:30782832; PMID:30509897). Early human gene-transfer experience in pediatric DFNB9 patients, including AAV1-hOTOF delivery, has now shown hearing improvement signals (PMID:38280389), and ongoing trials continue to enroll (NCT:NCT05788536; NCT:NCT05821959). Because p.Arg1227Ter is a stop-gain allele in a biallelic loss-of-function disorder, providing a complete otoferlin coding sequence avoids the instability and heterogeneity of mutant transcripts.

The available human data remain early-phase and disease-level rather than specific to p.Arg1227Ter, so this should be read as a mechanism-based supporting argument, not clinical validation of this allele. Clinical benefit depends on confirming biallelic OTOF disease, cochlear target-cell viability, surgical delivery quality, and optimal pediatric timing; durability and re-dosing constraints also remain unresolved for current AAV platforms.