Pathogenic missense variants in COCH are associated with DFNA9, an autosomal dominantly inherited type of progressive sensorineural hearing loss with or without vestibular dysfunction. This study is a comprehensive overview of genotype-phenotype correlations using the PRISMA and HuGENet guidelines. Study characteristics, risk of bias, genotyping and data on the self-reported age of onset, symptoms of vestibular dysfunction, normative test results for vestibular function, and results of audiovestibular examinations were extracted for each underlying pathogenic COCH variant. The literature search yielded 48 studies describing the audiovestibular phenotypes of 27 DFNA9-associated variants in COCH. Subsequently, meta-analysis of audiometric data was performed by constructing age-related typical audiograms and by performing non-linear regression analyses on the age of onset and progression of hearing loss. Significant differences were found between the calculated ages of onset and progression of the audiovestibular phenotypes of subjects with pathogenic variants affecting either the LCCL domain of cochlin or the vWFA2 and Ivd1 domains. We conclude that the audiovestibular phenotypes associated with DFNA9 are highly variable. Variants affecting the LCCL domain of cochlin generally lead to more progression of hearing loss when compared to variants affecting the other domains. This review serves as a reference for prospective natural history studies in anticipation of mutation-specific therapeutic interventions.

Objective: The objective of this study was to assess the safety and tolerability of the intratympanic delivery of AC102, a novel pharmaceutical therapy based on a thermosensitive gel for preventing and treating a range of hearing impairments, including sudden sensorineural hearing loss. We studied this in healthy, normal-hearing volunteers to evaluate any change in hearing thresholds. Study Design: An open-label, placebo-controlled, ascending single-dose, multicenter phase 1 clinical trial. Setting: The study was conducted in two centers (blinded for reviewing purposes). Subjects: Forty-two normal-hearing healthy volunteers younger than 40 years of age were eligible for enrollment in the study. Intervention: A single intratympanic injection of a thermosensitive gel, either a placebo or containing AC102, to the middle ear. Main Outcome Measure: The primary objective of this study was to assess the safety and tolerability of a single intratympanic injection of ascending volume of placebo and ascending volume and concentration of AC102. The secondary objective was to determine single-dose pharmacokinetics of intratympanically injected AC102 and to evaluate any change in hearing thresholds in healthy male and female subjects. Results: The intratympanic delivery of AC102 thermogel was safe and well tolerated in healthy volunteers with normal hearing, with no permanent adverse events recorded. A mild and temporary volume-dependent conductive hearing loss in the higher frequencies was observed irrespective of AC102 or placebo, which did not result in long-term changes in hearing. Other transient adverse events related to the injection procedure were largely similar between placebo gel and AC102 suspension, consisting mainly of mild ear discomfort, tinnitus, otalgia, and the formation of a droplet of blood at the injection site. Conclusions: The results of this phase 1 clinical trial suggest that the intratympanic delivery of AC102 is a safe and well-tolerated approach for drug delivery to the inner ear in healthy volunteers with normal hearing. As temporary, volume-dependent, conductive hearing losses were observed in the higher frequencies, it is recommended that patients are counseled on a short-term increase in hearing thresholds following injection for conditions such as sudden hearing loss.

Objective: To evaluate long-term outcomes of cochlear implantation (CI) in DFNA9 patients with the p.Pro51Ser COCH variant, compared with matched controls, and to identify clinical predictors of performance and quality of life (QoL). Background: DFNA9, caused by pathogenic variants in the COCH gene, is a progressive hereditary hearing loss with variable vestibular dysfunction that often necessitates cochlear implantation. Methods: In this retrospective cohort study, 56 DFNA9 patients were compared with case-matched postlingually deaf CI recipients without hereditary hearing loss. Speech perception, pure-tone thresholds, and QoL (Nijmegen Cochlear Implant Questionnaire, Glasgow Benefit Inventory) were assessed preimplantation and at 6 weeks, 1 year, and 5 years. Linear and mixed-effects models were applied to identify predictors and longitudinal changes. Results: Cochlear implantation significantly improved speech perception and QoL in both groups, with no differences between DFNA9 and controls and stable performance up to 5 years. Postoperative residual hearing (PTA₀.₅–2 kHz) was a significant predictor of 1-year speech perception. In DFNA9, higher preoperative aided speech perception was more strongly associated with postoperative outcomes, underscoring the advantage of implantation before further decline. Speech perception scores predicted QoL, although the link with perceived social benefit was weaker in DFNA9 than in controls. Conclusions: CI provides durable, noninferior outcomes in DFNA9 patients compared with controls. Although the study did not examine the impact of hearing loss severity or rate of decline, the excellent outcomes observed in this cohort may help clinicians to consider earlier implantation.

Objective: This study aims to analyze the progression of hearing loss using prospectively collected data and describe the vestibular phenotype of Usher syndrome type 2A (USH 2a ). Study Design: Longitudinal, prospective, observational natural history study. Patients: Patients with USH2a and USH2A -associated non-syndromic retinitis pigmentosa (nsRP). Main Outcome Measures: Hearing loss progression was measured by pure tone audiometry (PTA) and phoneme scores. Vestibular function was assessed by velocity step tests (VSTs), video head impulse tests (vHITs), caloric reflex tests, and vestibular evoked myogenic potentials (VEMPs). Patient-reported symptoms were assessed by questionnaires (Usher Lifestyle Survey, SF-12, PHQ-9, DHI, and SSQ). Results: Thirty-three patients with USH2a and 2 patients with nsRP were included. PTA _0.5-4kHz thresholds showed a significant decrease of 2.3 dB ( P =0.017) over 4 years. The progression of hearing loss was most pronounced in the mid-to-high frequencies. No significant differences were observed in phoneme scores as measured by the Speech Reception Threshold (SRT). The 2 patients with nsRP had normal hearing. Vestibular evaluation showed abnormal cervical VEMPs in 34% and abnormal ocular VEMPs in 75% of USH2a patients. VSTs, caloric reflex tests, and vHIT results were within normal limits in more than 90% of subjects. Patient questionnaires revealed no major balance problems as indicated by the DHI. Conclusions: This analysis provides robust evidence of measurable hearing loss progression in PTA _0.5-4kHz thresholds in USH2a patients beyond presbycusis. Speech understanding, as measured by SRT, remains relatively stable. Vestibular evaluation revealed no semicircular canal dysfunction, although VEMP results suggest a potential subclinical otolith organ impairment in USH2a patients.