The natural history and genotype-phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis.

TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype-phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.

Cochlear Implant Referral Criteria for the Spanish-Speaking Adult Population.

OBJECTIVE: To evaluate the effectiveness of the "60/60 Guideline" in a diverse patient population. STUDY DESIGN: Retrospective review. SETTING: Tertiary referral center. PATIENTS: Data were collected for adult patients (18 years and older) who underwent a cochlear implant evaluation (CIE) between January 2016 and March 2021. MAIN OUTCOME MEASURES: Development of the "60/60 Guideline" has provided better clarity on when to refer English-speaking patients for a CIE. Our study evaluated the effectiveness of this referral tool in the Spanish-speaking population. RESULTS: In our group of patients who underwent a traditional CIE (n = 402), 209 met unaided and aided traditional cochlear implant (CI) candidacy criteria. Of the 193 individuals who did not meet both components of traditional candidacy criteria, a majority met the aided component (86%) but only 4.6% met the unaided component. When applying the 60/60 Guideline to patients who met traditional criteria, there is a sensitivity rating of 84.7% and a specificity index of 50.3%. For English and Spanish speakers who met traditional criteria but did not meet the 60/60 Guideline, a majority (83.3% English, 87.5% Spanish) had a better ear word recognition score (WRS) greater than 60%, suggesting the unaided WRS is the more restrictive component of the "60/60 Guideline." CONCLUSION: Application of the "60/60 Guideline" is an effective method to identify potential CI candidates in the English-speaking population; however, it was less effective in the Spanish-speaking population. Spanish-speaking adults should be referred for a CIE when better ear pure tone average is greater than 60 dB hearing loss, regardless of their unaided WRS. This study highlights the need for inclusion of nonlinguistic test measures in the CI referral criteria and test battery to reduce CI access barriers for patients who speak a language other than English.

Effects of Bilateral Cochlear Implantation on Binaural Listening Tasks for Younger and Older Adults.

PURPOSE: This study investigated the objective and subjective benefit of a second cochlear implant (CI) on binaural listening tasks of speech understanding in noise and localization in younger and older adults. We aimed to determine if the aging population can utilize binaural cues and obtain comparable benefits from bilateral CI (BIL_CI) when compared to the younger population. METHODS: Twenty-nine adults with severe to profound bilateral sensorineural hearing loss were included. Participants were evaluated in two conditions, better CI (BE_CI) alone and BIL_CI using AzBio and Bamford-Kowal-Bench (BKB) sentence in noise tests. Localization tasks were completed in the BIL_CI condition using a broadband stimulus, low-frequency stimuli, and high-frequency stimuli. A subjective questionnaire was administered to assess satisfaction with CI. RESULTS: Older age was significantly associated with poorer performance on AzBio +5 dB signal-to-noise ratio (SNR) and BKB-speech in noise (SIN); however, improvements from BE_CI to BIL_CI were observed across all ages. In the AzBio +5 condition, nearly half of all participants achieved a significant improvement from BE_CI to BIL_CI with the majority of those occurring in patients younger than 65 years of age. Conversely, the majority of participants who achieved a significant improvement in BKB-SIN were adults >65 years of age. Years of BIL_CI experience and time between implants were not associated with performance. For localization, mean absolute error increased with age for low and high narrowband noise, but not for the broadband noise. Response gain was negatively correlated with age for all localization stimuli. Neither BIL_CI listening experience nor time between implants significantly impacted localization ability. Subjectively, participants report reduction in disability with the addition of the second CI. There is no observed relationship between age or speech recognition score and satisfaction with BIL_CI. CONCLUSION: Overall performance on binaural listening tasks was poorer in older adults than in younger adults. However, older adults were able to achieve significant benefit from the addition of a second CI, and performance on binaural tasks was not correlated with overall device satisfaction. The significance of the improvement was task and stimulus dependent but suggested a critical limit may exist for optimal performance on SIN tasks for CI users. Specifically, older adults require at least a +8 dB SNR to understand 50% of speech postoperatively; therefore, solely utilizing a fixed +5 dB SNR preoperatively to qualify CI candidates is not recommended as this test condition may introduce limitations in demonstrating CI benefit.

Screening Strategies for Deafness Genes and Functional Outcomes in Cochlear Implant Patients.

OBJECTIVES: To review the current state of knowledge about the influence of specific genetic mutations that cause sensorineural hearing loss (SNHL) on cochlear implant (CI) functional outcomes, and how this knowledge may be integrated into clinical practice. A multistep and sequential population-based genetic algorithm suitable for the identification of congenital SNHL mutations before CI placement is also examined. DATA SOURCES, STUDY SELECTION: A review was performed of the English literature from 2000 to 2019 using PubMed regarding the influence of specific mutations on CI outcomes and the use of next-generation sequencing for genetic screening of CI patients. CONCLUSION: CI is an effective habilitation option for patients with severe-profound congenital SNHL. However, it is well known that CI outcomes show substantial inter-patient variation. Recent advances in genetic studies have improved our understanding of genotype-phenotype relationships for many of the mutations underlying congenital SNHL, and have explored how these relationships may account for some of the variance seen in CI performance outcomes. A sequential genetic screening strategy utilizing next-generation sequencing-based population-specific gene panels may allow for more efficient mutation identification before CI placement. Understanding the relationships between specific mutations and CI outcomes along with integrating routine comprehensive genetic testing into pre-CI evaluations will allow for more effective patient counseling and open the door for the development of mutation-specific treatment strategies.

Genetics and the Individualized Therapy of Vestibular Disorders.

Background: Vestibular disorders (VDs) are a clinically divergent group of conditions that stem from pathology at the level of the inner ear, vestibulocochlear nerve, or central vestibular pathway. No etiology can be identified in the majority of patients with VDs. Relatively few families have been reported with VD, and so far, no causative genes have been identified despite the fact that more than 100 genes have been identified for inherited hearing loss. Inherited VDs, similar to deafness, are genetically heterogeneous and follow Mendelian inheritance patterns with all modes of transmission, as well as multifactorial inheritance. With advances in genetic sequencing, evidence of familial clustering in VD has begun to highlight the genetic causes of these disorders, potentially opening up new avenues of treatment, particularly in Meniere's disease and disorders with comorbid hearing loss, such as Usher syndrome. In this review, we aim to present recent findings on the genetics of VDs, review the role of genetic sequencing tools, and explore the potential for individualized medicine in the treatment of these disorders. Methods: A search of the PubMed database was performed for English language studies relevant to the genetic basis of and therapies for vestibular disorders, using search terms including but not limited to: "genetics," "genomics," "vestibular disorders," "hearing loss with vestibular dysfunction," "individualized medicine," "genome-wide association studies," "precision medicine," and "Meniere's syndrome." Results: Increasing numbers of studies on vestibular disorder genetics have been published in recent years. Next-generation sequencing and new genetic tools are being utilized to unearth the significance of the genomic findings in terms of understanding disease etiology and clinical utility, with growing research interest being shown for individualized gene therapy for some disorders. Conclusions: The genetic knowledge base for vestibular disorders is still in its infancy. Identifying the genetic causes of balance problems is imperative in our understanding of the biology of normal function of the vestibule and the disease etiology and process. There is an increasing effort to use new and efficient genetic sequencing tools to discover the genetic causes for these diseases, leading to the hope for precise and personalized treatment for these patients.

Initial hearing preservation outcomes of cochlear implantation with a slim perimodiolar electrode array.

OBJECTIVE: To assess the slim modiolar array as a hearing preservation electrode. METHODS: Retrospective chart review of adult, post-lingual CI recipients implanted with slim modiolar array Sept 2016 to July 2017 in a tertiary referral center. Baseline audiograms were obtained within six months of initial CI evaluation. Patients with low frequency pure tone average (LFPTA) (125, 250, 500 Hz) <80 dB were considered HP candidates. Postoperative audiograms were obtained within 48 h before activation. Successful HP was considered as (1) retention of LFPTA threshold <80 dB and (2) change in threshold from pre- to post-operative. RESULTS: Sixty-three patients received the slim perimodiolar array and 42 were HP candidates. Post-operative audiograms were obtained for 39 of 42 patients an average of 28.92 days after surgery. 56.4% of HP candidates retainedLFPTA <80 dB. Mean ΔLFPTA was 24.15 dB (±16.14; p < 0.001). 56.4% of HP candidates experienced Δ LFPTA <20 dB; 69.2% <30 dB. Functional hearing preservation was more successful in lower frequencies where starting thresholds were better - 78% with LFPTA <50 dB retained serviceable hearing at activation. The postoperative change was similar in each low frequency (Δ125 Hz: mean 21.25 +/- 14.76 (N = 28); Δ250 Hz: 26.28 +/- 19.29 (N = 39); Δ500 Hz: 25.00 +/- 17.73 (N = 39)). CONCLUSIONS: The slim perimodiolar array is moderately effective at immediate hearing preservation. In subjects with preoperative audiometric profiles similar to those in prior EAS trials, immediate HP is comparable.

Slim Perimodiolar Arrays Are as Effective as Slim Lateral Wall Arrays for Functional Hearing Preservation After Cochlear Implantation.

OBJECTIVE: To compare functional hearing preservation (HP) with a slim perimodiolar array (SPA) and a slim lateral wall array (SLW) in cochlear implantation (CI). STUDY DESIGN: Retrospective chart review. SETTING: Tertiary referral center. PATIENTS: All adult, post-lingual CI recipients with serviceable preoperative hearing serially implanted with SPA or SLW electrodes from July 2015 through July 2018. INTERVENTIONS: Cochlear implantation. MAIN OUTCOME MEASURES: Hearing preservation (HP). Patients with a low frequency pure-tone average (LFPTA) (125, 250, 500 Hz) threshold less than 80 dB were considered HP candidates based on preoperative audiograms. Postoperative audiograms were obtained before activation. Successful HP was defined as retention of LFPTA less than 80 dB. The change in LFPTA (ΔLFPTA) was also calculated. RESULTS: One hundred twenty one patients were implanted with either the SPA or SLW electrodes, 82 (42,40) of whom were HP candidates with postoperative audiograms. Average (standard deviation, SD) preoperative LFPTA was 54.86 [19.38] and 54.38 [13.58] dB for SLW and SPA respectively, with a mean ΔLFPTA of 24.6 [15.94] and 24.92 [16.66] dB. Successful HP was achieved in 21 (50%) and 22 (55%). Preoperative LFTPA, ΔLFPTA, and postoperative LFPTA were not significantly different (p = 0.89, 0.75, 0.93) between electrodes. CONCLUSIONS: The SPA is as effective at immediate functional HP after CI as a SLW.