BackgroundIt is well established that biallelic mutations in transmembrane protease, serine 3 (TMPRSS3) cause hearing loss. Currently, there is controversy regarding the audiological outcomes after cochlear implantation (CI) for TMPRSS3-associated hearing loss. This controversy creates confusion among healthcare providers regarding the best treatment options for individuals with TMPRSS3-related hearing loss.MethodsA literature review was performed to identify all published cases of patients with TMPRSS3-associated hearing loss who received a CI. CI outcomes of this cohort were compared with published adult CI cohorts using postoperative consonant-nucleus-consonant (CNC) word performance. TMPRSS3 expression in mouse cochlea and human auditory nerves (HAN) was determined by using hybridisation chain reaction and single-cell RNA-sequencing analysis.ResultsIn aggregate, 27 patients (30 total CI ears) with TMPRSS3-associated hearing loss treated with CI, and 85% of patients reported favourable outcomes. Postoperative CNC word scores in patients with TMPRSS3-associated hearing loss were not significantly different than those seen in adult CI cohorts (8 studies). Robust Tmprss3 expression occurs throughout the mouse organ of Corti, the spindle and root cells of the lateral wall and faint staining within <5% of the HAN, representing type II spiral ganglion neurons. Adult HAN express negligible levels of TMPRSS3.ConclusionThe clinical features after CI and physiological expression of TMPRSS3 suggest against a major role of TMPRSS3 in auditory neurons.

Hearing loss and peripheral neuropathy are two clinical entities that are genetically and phenotypically heterogeneous and sometimes co-occurring. Using exome sequencing and targeted segregation analysis, we investigated the genetic etiology of peripheral neuropathy and hearing loss in a large Ashkenazi Jewish family. Moreover, we assessed the production of the candidate protein via western blotting of lysates from fibroblasts from an affected individual and an unaffected control. Pathogenic variants in known disease genes associated with hearing loss and peripheral neuropathy were excluded. A homozygous frameshift variant in the BICD1 gene, c.1683dup (p.(Arg562Thrfs*18)), was identified in the proband and segregated with hearing loss and peripheral neuropathy in the family. The BIDC1 RNA analysis from patient fibroblasts showed a modest reduction in gene transcripts compared to the controls. In contrast, protein could not be detected in fibroblasts from a homozygous c.1683dup individual, whereas BICD1 was detected in an unaffected individual. Our findings indicate that bi-allelic loss-of-function variants in BICD1 are associated with hearing loss and peripheral neuropathy. Definitive evidence that bi-allelic loss-of-function variants in BICD1 cause peripheral neuropathy and hearing loss will require the identification of other families and individuals with similar variants with the same phenotype.

OBJECTIVES To review the audiological outcomes after cochlear implantation (CI) for TMPRSS3-associated autosomal recessive non-syndromic hearing loss (ARNSHL) and evaluate the spatial expression pattern of TMPRSS3 within the human cochlea. METHODS Review all published cases of CI in patients with TMPRSS3-associated ARNSHL to compare postoperative consonant-nucleus-consonant (CNC) word performance to published adult CI cohorts. Protein structural modeling of TMPRSS3 variants associated with post-lingual hearing loss. Determine TMPRSS3 expression pattern in human inner ear organoids and human cochlea. RESULTS Nine articles detailed 27 patients (30 total CI ears) with TMPRSS3-associated hearing loss treated with CI. Of these, 6 cases reported prelingual onset (< 2yo) and 24 cases reported post-lingual onset (≥2yo) of hearing loss. Subjectively, 85% of cases had a favorable outcome. Objectively, the postoperative mean (SD) post-operative CNC word score was not significantly different than other adults [66.2% (25.8%) correct vs. 50.1% (12.5%); F(1,6) = 1.97, P = 0.21]. In the TMPRSS3 cohort, poor performers (CNC < 30% correct) were significantly older than good performers [49 (± 13.3) years vs. 17.4 (± 18.4) years; P < 0.01] and all harbored the A138E variant. TMPRSS3 immunostaining is restricted to the otic epithelial cells and is not expressed within auditory neurons of human cochlea and human inner ear organoids. CONCLUSIONS Patients with TMPRSS3-related hearing loss exhibit similar postoperative performance to other adult CI patients. TMPRSS3 is not expressed in human auditory neurons and the duration of hearing loss prior to CI likely contributes to poor performance.