Natural Course of Residual Hearing with Reference to GJB2 and SLC26A4 Genotypes: Clinical Implications for Hearing Rehabilitation.

BACKGROUND: Understanding the characteristics of residual hearing at low frequencies and its natural course in relation to molecular genetic etiology may be important in developing rehabilitation strategies. Thus, we aimed to explore the characteristics and natural course of residual hearing at low frequencies associated with the two most frequent deafness genes: GJB2 and SLC26A4. METHODS: Initially, 53 GJB2 and 65 SLC26A4 subjects were enrolled, respectively. Only those whose audiograms exhibited hearing thresholds ≤70 dB at 250 and 500 Hz, and who had at least 1-year follow-up period between the first and last audiograms, were included. Collectively, the clinical characteristics of 14 ears from eight subjects with GJB2 variants, and 31 ears from 22 subjects with SLC26A4 variants fulfilled the strict criteria. In this study, a dropout rate refers to an incidence of dropping out of the cohort by cochlear implant surgery due to severe hearing deterioration. RESULTS: Among the ears with complete serial audiogram data set, significant residual hearing at low frequencies at the time of inclusion was observed in 18.8% of those with GJB2 variants (15 out of 80 ears) and 42.6% of those with SLC26A4 variants (46 out of 108 ears), revealing a difference between two deafness genes. Subsequently, ears with SLC26A4 variants (11 of 46 ears, 23.9%) turned out to have a higher dropout rate for cochlear implantation due to hearing deterioration within the first year than those with GJB2 variants (1 of 15, 6.7%), albeit with no statistical significance. Throughout the follow-up period (mean: 37.2 ± 6.8, range: 12 to 80 months), deterioration of residual hearing at low frequencies at 250 Hz (dB HL/y) and 500 Hz (dB HL/y) of those with GJB2 variants exhibited 3.1 ± 1.3 (range: 0 to 15) and 5.2 ± 1.6 (range: 0 to 20), respectively, suggesting the deterioration of residual hearing in GJB2 variants was rather slow and gradual. Specifically, GJB2 p.Leu79Cysfs*3 show less remarkable residual hearing at low frequencies, but then a relatively stable nature. In contrast, SLC26A4 variants demonstrated a significantly higher dropout rate due to severe hearing deterioration requiring cochlear implantation compared with the GJB2 variants. This trend was observed not only in the first-year follow-up period but also in the follow-up periods thereafter. The p.His723Arg;c.919-2A>G genotype of SLC26A4, in particular, was associated with a high propensity for sudden hearing deterioration, as indicated by the dropout rate, which was as high as 46.2% for cochlear implantation due to hearing deterioration during the first year follow-up period. Furthermore, the dropout rate for cochlear implantation was observed in 7.1% of those with GJB2 variants (one out of 14 ears) and 30.3% of those with SLC26A4 variants (10 out of 33 ears) throughout the entire follow-up period. CONCLUSIONS: Our results suggest that there is a difference with respect to the progressive nature of residual hearing at low frequencies between the two most common genes responsible for hearing loss, which may provide clinical implications of having individualized rehabilitation and timely intervention.

Improving genetic diagnosis by disease-specific, ACMG/AMP variant interpretation guidelines for hearing loss.

The 2018 Hearing Loss Expert Panel (HL-EP)-specific guidelines specified from the universal 2015 ACMG/AMP guidelines are proposed to be used in genetic HL, which prompted this study. A genetic HL cohort comprising 135 unrelated probands with available exome sequencing data was established. Overall, 169 variants were prioritized as candidates and interpreted using the 2015 ACMG/AMP and 2018 HL-EP guidelines. Changes in rule application and variant classification between the guidelines were compared. The concordance rate of variant classification of each variant between the guidelines was 71.60%, with significant difference. The proportion of pathogenic variants increased from 13.02% (2015) to 29.59% (2018). Variant classifications of autosomal recessive (AR) variants that previously belonged to VUS or likely pathogenic in the 2015 guidelines were changed toward pathogenic in the 2018 guidelines more frequently than those of autosomal dominant variants (29.17% vs. 6.38%, P = 0.005). Stratification of the PM3 and PP1 rules in the 2018 guidelines led to more substantial escalation than that in the 2015 guidelines. We compared the disease-specific guidelines (2018) with the universal guidelines (2015) using real-world data. Owing to the sophistication of case-level data, the HL-specific guidelines have more explicitly classified AR variants toward "likely pathogenic" or "pathogenic", serving as potential references for other recessive genetic diseases.

Central auditory maturation and behavioral outcomes after cochlear implantation in prelingual auditory neuropathy spectrum disorder related to OTOF variants (DFNB9): Lessons from pilot study.

The cortical auditory evoked potential (CAEP)-based P1 component acts as a biomarker for cochlear implantation (CI) outcomes in children with auditory neuropathy spectrum disorder (ANSD). To date, early intervention primarily before the age of two years and six months of CI usage is necessary and sufficient to achieve age-appropriate cortical maturation and good prognosis. However, varying degrees of neural dyssynchrony, resulting from the etiological heterogeneity of ANSD, may preclude uniform application of this hypothesis to ensure auditory cortical maturation. Thus, a focused evaluation of those carrying OTOF variants, which may be the salient molecular etiology of prelingual ANSD, would circumvent the issue of heterogeneity. Here, we sought to provide a much better understanding of the brain perspectives (i.e., P1 maturation) in OTOF-associated ANSD subjects and set the stage for an optimal strategy to enhance language development. We conducted a preliminary study comprising 10 subjects diagnosed with OTOF-related ANSD who underwent CI by a single surgeon and subsequently underwent measurements of the P1 component. We observed that DFNB9 subjects who received CI after 2 years of age exhibited "absent" or "anomalous" P1 components that correspond to delayed language development. However, timely implantation, as early as 12 months of age per se, might be insufficient to achieve age-appropriate cortical maturation of DFNB9 in cases with six to seven months of device use. This suggests the importance of sustained rehabilitation in DFNB9 than in other etiologies. Indeed, an additional follow-up study showed that a reduction in P1 latency was linked to an improvement in auditory performance. Collectively, our results suggest that central auditory maturation and successful outcome of CI in DFNB9 may have more demanding requirements, that is, earlier implantation and more sustained rehabilitation. We believe that the current study opens a new path toward genome-based neuroimaging in the field of hearing research.

Outcome of cochlear implantation in the worse ear of post-lingual asymmetric hearing loss: elucidation of prognostic markers.

BACKGROUND: Specific correlations between the outcomes of cochlear implantation (CI) and hearing thresholds of the both ears in post-lingual asymmetric hearing loss (AHL) patients were not clear. AIMS/OBJECTIVES: To identify the variables influencing the outcome of CI in post-lingual AHL patients. METHOD: We included 18 adult subjects who had CI in the worse ear due to post-lingual AHL with average hearing asymmetry of 36 dB. Speech perception scores were evaluated in the sound field with hearing aid on the better ear before CI, and with the cochlear implant in the worse ear at 3, 6, and 12 months after CI switch-on. RESULTS: Average increases in phonetically balanced word score, spondee word score, and everyday sentence score at 12 months from CI switch-on compared with those before CI were 38.9%p, 46.2%p, and 52.4%p, respectively. Multiple linear regression analysis showed that speech perception scores were negatively influenced by age at implantation and hearing threshold difference of both ears (HTD-Both) itself, rather than the worse or better ear hearing thresholds. CONCLUSIONS AND SIGNIFICANCE: Post-lingual AHL subjects with high average hearing asymmetry can benefit from CI in the worse ear, while CI outcomes can be adversely influenced by HTD-Both and age at implantation both in the short- and long-term follow-up.

Powerful use of automated prioritization of candidate variants in genetic hearing loss with extreme etiologic heterogeneity.

Variant prioritization of exome sequencing (ES) data for molecular diagnosis of sensorineural hearing loss (SNHL) with extreme etiologic heterogeneity poses a significant challenge. This study used an automated variant prioritization system ("EVIDENCE") to analyze SNHL patient data and assess its diagnostic accuracy. We performed ES of 263 probands manifesting mild to moderate or higher degrees of SNHL. Candidate variants were classified according to the 2015 American College of Medical Genetics guidelines, and we compared the accuracy, call rates, and efficiency of variant prioritizations performed manually by humans or using EVIDENCE. In our in silico panel, 21 synthetic cases were successfully analyzed by EVIDENCE. In our cohort, the ES diagnostic yield for SNHL by manual analysis was 50.19% (132/263) and 50.95% (134/263) by EVIDENCE. EVIDENCE processed ES data 24-fold faster than humans, and the concordant call rate between humans and EVIDENCE was 97.72% (257/263). Additionally, EVIDENCE outperformed human accuracy, especially at discovering causative variants of rare syndromic deafness, whereas flexible interpretations that required predefined specific genotype-phenotype correlations were possible only by manual prioritization. The automated variant prioritization system remarkably facilitated the molecular diagnosis of hearing loss with high accuracy and efficiency, fostering the popularization of molecular genetic diagnosis of SNHL.