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.

Vestibular Preservation in Pediatric Cochlear Implantation.

OBJECTIVES: Evaluate the rate of preserved vestibular function in pediatric cochlear implant surgery. STUDY DESIGN: Retrospective case review. METHODS: Pre- and post-operative vestibular tests were compared in children who underwent cochlear implantation at a tertiary level pediatric hospital over a 4-year period. RESULTS: Data from 59 implanted ears in 44 children was included. Median age was 2.8 years at initial testing (range 7 months - 21 years) with 1:1 male/female ratio. Implant surgeries were 26 unilateral, 13 bilateral simultaneous, and 5 bilateral sequential. The majority were implanted with slim, non-styletted electrodes (86.4%) via a round window approach (91.5%). Normal pre-operative results were preserved post-operatively on rotary chair testing in 75% (21/28) of patients, cervical vestibular evoked myogenic potential testing in (75%) 30/40 of ears tested, ocular vestibular evoked myogenic potential testing in 85.7% (6/7) of ears tested, video head impulse testing in 100% (9/9) of ears tested, and computerized dynamic posturography in 100% (5/5) of patients tested. Overall, 62.5% of patients had no new deficits on any vestibular test performed post-operatively. CONCLUSIONS: Preservation rates of vestibular function following cochlear implant surgery were higher in this cohort than what has been reported in many earlier studies. Contemporary, less traumatic electrodes and insertion techniques may be a significant factor. The risk of causing a new, severe bilateral vestibular loss with long-term functional impacts appears to be low. Further study is warranted on the impacts of different cochlear implant electrode designs and insertion approaches on post-operative vestibular preservation. LEVEL OF EVIDENCE: 4, Case Series Laryngoscope, 134:1913-1918, 2024.

High prevalence of syndromic hearing loss in Mexican children undergoing cochlear implantation.

Objective: Studies evaluating genetic sensorineural hearing loss (SNHL) in Hispanic and Latino populations using genomic technologies are lacking. Recent data has shown that Hispanic and Latino children display lower genetic diagnostic rates despite similar prevalence rates of SNHL to their Asian and White counterparts, thus negatively affecting their clinical care. Our objective was to determine the genetic contribution to SNHL in a population of Mexican children undergoing evaluation for cochlear implantation. Methods: Pediatric patients from Mexico with severe to profound SNHL undergoing evaluation for cochlear implantation were recruited. Exome sequencing (ES) or hearing loss gene panel testing was performed. Variant pathogenicity was established in accordance to criteria established by the American College of Medical Genetics, and variants of interest were clinically confirmed via CLIA certified laboratory. Results: Genetic evaluation was completed for 30 Mexican children with severe to profound SNHL. A genetic cause was identified for 47% (14) of probands, and 7% (2) probands had an inconclusive result. Of the diagnoses, 10 (71%) were syndromic or likely syndromic, and 4 (29%) were nonsyndromic. Eight probands (80% of all syndromic diagnoses) were diagnosed with a syndromic form of hearing loss that mimics a nonsyndromic clinical presentation at a young age and so could not be suspected based on clinical evaluation alone without genetic testing. Conclusion: This is the largest study to date to use comprehensive genomic testing for the evaluation of Mexican children with severe to profound SNHL. A significant proportion of children in this cohort were diagnosed with syndromic hearing loss. Future study in a larger cohort of Mexican children with varying degrees of hearing loss is required to improve the efficacy of genetic testing and timely medical intervention within these ethnically diverse populations. Level of evidence: Level 4 (cohort study).

Exome Sequencing Expands the Genetic Diagnostic Spectrum for Pediatric Hearing Loss.

OBJECTIVES: Genetic testing is the standard-of-care for diagnostic evaluation of bilateral, symmetric, sensorineural hearing loss (HL). We sought to determine the efficacy of a comprehensive genetic testing method, exome sequencing (ES), in a heterogeneous pediatric patient population with bilateral symmetric, bilateral asymmetric, and unilateral HL. METHODS: Trio-based ES was performed for pediatric patients with confirmed HL including those with symmetric, asymmetric, and unilateral HL. RESULTS: ES was completed for 218 probands. A genetic cause was identified for 31.2% of probands (n = 68). The diagnostic rate was 40.7% for bilateral HL, 23.1% for asymmetric HL, and 18.3% for unilateral HL, with syndromic diagnoses made in 20.8%, 33.3%, and 54.5% of cases in each group, respectively. Secondary or incidental findings were identified in 10 families (5.52%). CONCLUSION: ES is an effective method for genetic diagnosis for HL including phenotypically diverse patients and allows the identification of secondary findings, discovery of deafness-causing genes, and the potential for efficient data re-analysis. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:2417-2424, 2023.

The Importance of Accessible Language for Development in Deaf and Hard of Hearing Children.

CASE: Brady is a 5-year-old boy who was seen in a multidisciplinary clinic for evaluation of deaf and hard of hearing children. Brady was born full-term after an uncomplicated pregnancy. He was referred for audiological evaluation after his newborn hearing screen and was diagnosed with a severe-to-profound bilateral sensorineural hearing difference at age 6 months. He has no other medical history.Brady was referred for developmental evaluation after completing his medical workup and cochlear implantation at an outside institution. No etiologic cause of his hearing difference was identified, and his diagnosis was presumed to be genetic and nonsyndromic. He had previously undergone right cochlear implantation at age 14 months and left cochlear implantation at age 23 months. Brady received speech and language therapy, with an emphasis on spoken language through early intervention, and met all motor and social milestones at appropriate times. Despite therapy, he continued to show delays in meeting language and communication milestones. Given concerns over persistent language delays after cochlear implantation, he underwent an interdisciplinary speech, language, and psychological evaluation at 3 years 4 months old. At the time of his evaluation, he was noted to have robust social skills but significantly delayed expressive and receptive language skills with language use limited to single words.After the initial evaluation, he was enrolled at a school for the deaf with instruction provided in both spoken English and American Sign Language. In follow-up evaluation at age 4 years 8 months, Brady was described as happy, cooperative, and eager to connect socially. It was noted that he had age-appropriate visual spatial cognitive and motor skills and had made some gains compared with prior assessments in both spoken and sign language. Notably, however, his language abilities and most areas of adaptive living skills remained below what would be expected by his developmental age and in some domains plateaued compared with prior assessments. He was able to produce some words and signs and responded to all prompts using only single words or signs and gestures. Brady's parents present today to your multidisciplinary clinic asking to understand why his language has not progressed further and to learn how they can help him reach his full potential.