RESUMO
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.
Assuntos
Estudos de Associação Genética , Perda Auditiva , Proteínas de Membrana , Serina Endopeptidases , Humanos , Feminino , Masculino , Serina Endopeptidases/genética , Adulto , Proteínas de Membrana/genética , Perda Auditiva/genética , Criança , Pessoa de Meia-Idade , Adolescente , Pré-Escolar , Genótipo , Estudos de Coortes , Fenótipo , Mutação de Sentido Incorreto , Estudos Transversais , Adulto Jovem , Estudos Retrospectivos , Idoso , Proteínas de NeoplasiasRESUMO
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.