Otoprotection against aminoglycoside- and cisplatin-induced ototoxicity focusing on the upstream drug uptake pathway.

Aminoglycoside- and cisplatin-induced ototoxicity, which is a significant issue owing to the widespread use of these drugs in clinical practice, involves the entry of aminoglycosides and cisplatin into the endolymph and hair cells via specific channels or transporters, followed by reactive oxygen species (ROS) generation and hair cells apoptosis. Current strategies focalize primarily on interference with downstream ROS effects; however, recent evidence has demonstrated that inhibiting the uptake of aminoglycosides and cisplatin by hair cells is another promising strategy for tackling the upstream drug uptake pathway. With advances in structural biology, the conformations of certain aminoglycoside and cisplatin channels and transporters, such as the mechanoelectrical transduction channel and organic cation transporter-2, have been largely elucidated. These channels and transporters may become potential targets for the introduction of new otoprotective strategies. This review focuses on the strategies for inhibiting ototoxic drugs uptake by auditory hair cells and provides potential targets for recent developments in the field of otoprotection. Molecular dynamics (MD) simulations of these proteins could help identify the molecules that inhibit the uptake of aminoglycosides and cisplatin by hair cells. Integrating upstream drug uptake pathway targets and MD simulations may help dissect molecular mechanisms and develop novel otoprotective strategies for aminoglycoside- and cisplatin-induced ototoxicity.

Simulation-predicted and -explained inheritance model of pathogenicity confirmed by transgenic mice models.

Variants in the gap junction beta-2 (GJB2) gene are the most common cause of hereditary hearing impairment. However, how GJB2 variants lead to local physicochemical and structural changes in the hexameric ion channels of connexin 26 (Cx26), resulting in hearing impairment, remains elusive. In this study, using molecular dynamics (MD) simulations, we showed that detached inner-wall N-terminal "plugs" aggregated to reduce the channel ion flow in a highly prevalent V37I variant in humans. To examine the predictive ability of the computational platform, an artificial mutant, V37M, of which the effect was previously unknown in hearing loss, was created. Microsecond simulations showed that homo-hexameric V37M Cx26 hemichannels had an abnormal affinity between the inner edge and N-termini to block the narrower side of the cone-shaped Cx26, while the most stable hetero-hexameric channels did not. From the perspective of the conformational energetics of WT and variant Cx26 hexamers, we propose that unaffected carriers could result from a conformational predominance of the WT and pore-shrinkage-incapable hetero-hexamers, while mice with homozygous variants can only harbor an unstable and dysfunctional N-termini-blocking V37M homo-hexamer. Consistent with these predictions, homozygous V37M transgenic mice exhibited apparent hearing loss, but not their heterozygous counterparts, indicating a recessive inheritance mode. Reduced channel conductivity was found in Gjb2V37M/V37M outer sulcus and Claudius cells but not in Gjb2WT/WT cells. We view that the current computational platform could serve as an assessment tool for the pathogenesis and inheritance of GJB2-related hearing impairments and other diseases caused by connexin dysfunction.

Genetic Factors Contribute to the Phenotypic Variability in GJB2-Related Hearing Impairment.

Recessive variants in GJB2 are the most important genetic cause of sensorineural hearing impairment (SNHI) worldwide. Phenotypes vary significantly in GJB2-related SNHI, even in patients with identical variants. For instance, patients homozygous for the GJB2 p.V37I variant, which is highly prevalent in the Asian populations, usually present with mild-to-moderate SNHI; yet severe-to-profound SNHI is occasionally observed in approximately 10% of p.V37I homozygotes. To investigate the genomic underpinnings of the phenotypic variability, we performed next-generation sequencing of GJB2 and other deafness genes in 63 p.V37I homozygotes with extreme phenotypic severities. We identified additional pathogenic variants of other deafness genes in 5 of the 35 patients with severe-to-profound SNHI. Furthermore, we conducted case-control association analyses for 30 unrelated p.V37I homozygotes with severe-to-profound SNHI against 28 p.V37I homozygotes with mild-to-moderate SNHI, and 120 population controls from the Taiwan Biobank. We found that the severe-to-profound group had a higher frequency of the crystallin lambda 1 (CRYL1) variant (rs14236), located upstream of GJB2, than the mild-to-moderate and Taiwan Biobank groups. Our results demonstrated that pathogenic variants in other deafness genes and a possible modifier, the CRYL1 rs14236 variant, may contribute to phenotypic variability in GJB2-realted SNHI, highlighting the importance of comprehensive genomic surveys to delineate the genotype-phenotype correlations.

Genetic Underpinnings and Audiological Characteristics in Children With Unilateral Sensorineural Hearing Loss.

OBJECTIVE: Unilateral sensorineural hearing loss (USNHL) is a condition commonly encountered in otolaryngology clinics. However, its molecular pathogenesis remains unclear. This study aimed to investigate the genetic underpinnings of childhood USNHL and analyze the associated audiological features. STUDY DESIGN: Retrospective analysis of a prospectively recruited cohort. SETTING: Tertiary referral center. METHODS: We enrolled 38 children with USNHL between January 1, 2018, and December 31, 2021, and performed physical, audiological, imaging, and congenital cytomegalovirus (cCMV) examinations as well as genetic testing using next-generation sequencing (NGS) targeting 30 deafness genes. The audiological results were compared across different etiologies. RESULTS: Causative genetic variants were identified in 8 (21.1%) patients, including 5 with GJB2 variants, 2 with PAX3 variants, and 1 with the EDNRB variant. GJB2 variants were found to be associated with mild-to-moderate USNHL in various audiogram configurations, whereas PAX3 and EDNRB variants were associated with profound USNHL in flat audiogram configurations. In addition, whole-genome sequencing and extended NGS targeting 213 deafness genes were performed in 2 multiplex families compatible with autosomal recessive inheritance; yet no definite causative variants were identified. Cochlear nerve deficiency and cCMV infection were observed in 9 and 2, respectively, patients without definite genetic diagnoses. CONCLUSION: Genetic underpinnings can contribute to approximately 20% of childhood USNHL, and different genotypes are associated with various audiological features. These findings highlight the utility of genetic examinations in guiding the diagnosis, counseling, and treatment of USNHL in children.

Revisiting Genetic Epidemiology with a Refined Targeted Gene Panel for Hereditary Hearing Impairment in the Taiwanese Population.

Hearing impairment is one of the most common sensory disorders in children, and targeted next-generation sequencing (NGS)-based genetic examinations can assist in its prognostication and management. In 2020, we developed a simplified 30-gene NGS panel from the original 214-gene NGS version based on Taiwanese genetic epidemiology data to increase the accessibility of NGS-based examinations. In this study, we evaluated the diagnostic performance of the 30-gene NGS panel and compared it with that of the original 214-gene NGS panel in patient subgroups with different clinical features. Data on the clinical features, genetic etiologies, audiological profiles, and outcomes were collected from 350 patients who underwent NGS-based genetic examinations for idiopathic bilateral sensorineural hearing impairment between 2020 and 2022. The overall diagnostic yield was 52%, with slight differences in genetic etiology between patients with different degrees of hearing impairment and ages of onset. No significant difference was found in the diagnostic yields between the two panels, regardless of clinical features, except for a lower detection rate of the 30-gene panel in the late-onset group. For patients with negative genetic results, where the causative variant is undetectable on current NGS-based methods, part of the negative results may be due to genes not covered by the panel or yet to be identified. In such cases, the hearing prognosis varies and may decline over time, necessitating appropriate follow-up and consultation. In conclusion, genetic etiologies can serve as references for refining targeted NGS panels with satisfactory diagnostic performance.

Generation of induced pluripotent stem cells (IBMSi027-A) from a patient with hearing loss carrying WFS1 c.2051C > T (p.Ala684Val) variant.

Pathogenic variants of the WFS1 gene can cause recessive-inherited Wolfram syndrome or dominant-inherited Wolfram-like syndrome with optic atrophy and hearing impairment. Using the Sendai virus delivery system, we generated induced pluripotent stem cells from the peripheral blood mononuclear cells of a female patient with the WFS1 pathogenic variant c.2051C > T (p.Ala684Val). The resulting induced pluripotent stem cells exhibited a normal karyotype and pluripotency, as confirmed using immunofluorescence staining, and differentiated into three germ layers in vivo. This cellular model provides a useful platform for investigating the pathogenic mechanisms of both blindness and deafness related to WFS1 variants.

Worsening Rhinosinusitis as a Prognostic Factor for Patients with Nasopharyngeal Carcinoma: A Retrospective Study.

Rhinosinusitis is common in patients with nasopharyngeal carcinoma (NPC). Our study aimed to explore the role of rhinosinusitis severity in NPC prognosis. Medical records and radiologic examinations of 90 patients with NPC at a single medical center from 2009−2016 were retrospectively analyzed. The Lund−Mackay (L−M) score was obtained for each patient before and after 6 months of treatment. Rhinosinusitis diagnosis was based on L−M scores of ≥4. L−M score differences were calculated as pre-treatment rhinosinusitis (PRRS) minus post-treatment rhinosinusitis (PSRS). L−M score difference was sub-grouped into "L−M scores > 0", "L−M scores = 0", and "L−M scores < 0". Clinical staging of our patients based on the American Joint Committee on Cancer 7th edition were: stage I in nine, stage II in seventeen, stage III in twenty-two, and stage IV in forty-two patients; twenty-seven (30%) patients had died. PRRS incidence was 34.4%, and PSRS was 36.7%. Median of L−M scores difference was 0 (−2.2). L−M score difference was an independent prognostic factor for the overall survival of patients with NPC (p < 0.05). Therefore, worsening rhinosinusitis was a prognostic factor for patients with NPC. Clinicians should consider NPC as a warning sign of poor prognosis during routine follow-ups.

Identification of nine novel variants across PAX3, SOX10, EDNRB, and MITF genes in Waardenburg syndrome with next-generation sequencing.

BACKGROUND: Waardenburg syndrome (WS) is a hereditary, genetically heterogeneous disorder characterized by variable presentations of sensorineural hearing impairment and pigmentation anomalies. This study aimed to investigate the clinical features of WS in detail and determine the genetic causes of patients with clinically suspected WS. METHODS: A total of 24 patients from 21 Han-Taiwanese families were enrolled and underwent comprehensive physical and audiological examinations. We applied targeted next-generation sequencing (NGS) to investigate the potential causative variants in these patients and further validated the candidate variants through Sanger sequencing. RESULTS: We identified 19 causative variants of WS in our cohort. Of these variants, nine were novel and discovered in PAX3, SOX10, EDNRB, and MITF genes, including missense, nonsense, deletion, and splice site variants. Several patients presented with skeletal deformities, hypotonia, megacolon, and neurological disorders that were rarely seen in WS. CONCLUSION: This study revealed highly phenotypic variability in Taiwanese WS patients and demonstrated that targeted NGS allowed us to clarify the genetic diagnosis and extend the genetic variant spectrum of WS.

Gene therapy with a synthetic adeno-associated viral vector improves audiovestibular phenotypes in Pjvk-mutant mice.

Recessive PJVK mutations that cause a deficiency of pejvakin, a protein expressed in both sensory hair cells and first-order neurons of the inner ear, are an important cause of hereditary hearing impairment. Patients with PJVK mutations garner limited benefits from cochlear implantation; thus, alternative biological therapies may be required to address this clinical difficulty. The synthetic adeno-associated viral vector Anc80L65, with its wide tropism and high transduction efficiency in various inner ear cells, may provide a solution. We delivered the PJVK transgene to the inner ear of Pjvk mutant mice using the synthetic Anc80L65 vector. We observed robust exogenous pejvakin expression in the hair cells and neurons of the cochlea and vestibular organs. Subsequent morphologic and audiologic studies demonstrated significant restoration of spiral ganglion neuron density and hair cells in the cochlea, along with partial recovery of sensorineural hearing impairment. In addition, we observed a recovery of vestibular ganglion neurons and balance function to WT levels. Our study demonstrates the utility of Anc80L65-mediated gene delivery in Pjvk mutant mice and provides insights into the potential of gene therapy for PJVK-related inner ear deficits.

Generation of induced pluripotent stem cells from a patient with hearing loss carrying OPA1 c.1468T>C (p.Cys490Arg) variant.

Pathogenic variants of OPA1 have been associated with autosomal dominant optic atrophy (DOA), leading to optic, auditory, and other sensorineural neuropathies and myopathies. Using the Sendai virus delivery system, we generated induced pluripotent stem cells from the peripheral blood mononuclear cells of a female patient with the OPA1 pathogenic variant c.1468T>C (p.Cys490Arg). The resulting induced pluripotent stem cells exhibited a normal karyotype and pluripotency, as confirmed using immunofluorescence staining, and differentiated into three germ layers in vivo. This cellular model is a useful platform for investigating the pathogenic mechanisms of both blindness and deafness related to OPA1 variants.

Comprehensive Etiologic Analyses in Pediatric Cochlear Implantees and the Clinical Implications.

Cochlear implantation is the treatment of choice for children with profound sensorineural hearing impairment (SNHI), yet the outcomes of cochlear implants (CI) vary significantly across individuals. To investigate the CI outcomes in pediatric patients with SNHI due to various etiologies, we prospectively recruited children who underwent CI surgery at two tertiary referral CI centers from 2010 to 2021. All patients underwent comprehensive history taking, next generation sequencing (NGS)-based genetic examinations, and imaging studies. The CI outcomes were evaluated using Categories of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR) scores. Of the 160 pediatric cochlear implantees (76 females and 84 males) included in this study, comprehensive etiological work-up helped achieve clinical diagnoses in 83.1% (133/160) of the patients, with genetic factors being the leading cause (61.3%). Imaging studies identified certain findings in 31 additional patients (19.3%). Four patients (2.5%) were identified with congenital cytomegalovirus infection (cCMV), and 27 patients (16.9%) remained with unknown etiologies. Pathogenic variants in the four predominant non-syndromic SNHI genes (i.e., SLC26A4, GJB2, MYO15A, and OTOF) were associated with favorable CI outcomes (Chi-square test, p = 0.023), whereas cochlear nerve deficiency (CND) on imaging studies was associated with unfavorable CI outcomes (Chi-square test, p < 0.001). Our results demonstrated a clear correlation between the etiologies and CI outcomes, underscoring the importance of thorough etiological work-up preoperatively in pediatric CI candidates.

Cochlear Implantation Outcomes in Patients with Auditory Neuropathy Spectrum Disorder of Genetic and Non-Genetic Etiologies: A Multicenter Study.

With diverse etiologies and clinical features, the management of pediatric auditory neuropathy spectrum disorder (ANSD) is often challenging, and the outcomes of cochlear implants (CIs) are variable. This study aimed to investigate CI outcomes in pediatric patients with ANSD of different etiologies. Thirty-six children with ANSD who underwent cochlear implantation between 2001 and 2021 were included. Comprehensive etiological analyses were conducted, including a history review, next-generation sequencing-based genetic examinations, and imaging studies using high-resolution computed tomography and magnetic resonance imaging. Serial behavioral and speech audiometry were performed before and after surgery, and the outcomes with CI were evaluated using the Categories of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR) scores. By etiology, 18, 1, 1, and 10 patients had OTOF-related, WFS1-related, OPA1-related, and cochlear nerve deficiency (CND)-related ANSD, respectively. Six patients had no definite etiology. The average CI-aided behavioral threshold was 28.3 ± 7.8 dBHL, and those with CND-related ANSD were significantly worse than OTOF-related ANSD. The patients' median CAP and SIR scores were 6 and 4, respectively. Favorable CI outcomes were observed in patients with certain etiologies of ANSD, particularly those with OTOF (CAP/SIR scores 5-7/2-5), WFS1 (CAP/SIR score 6/5), and OPA1 variants (CAP/SIR score 7/5). Patients with CND had suboptimal CI outcomes (CAP/SIR scores 2-6/1-3). Identifying the etiologies in ANSD patients is crucial before surgery and can aid in predicting prognoses.

Cochlear implant mapping strategy to solve difficulty in speech recognition.

BACKGROUND: Cochlear implants (CIs) are viable treatment options in patients with severe to profound hearing loss. Speech recognition difficulties were reported in some CI recipients even with a good-aided hearing threshold. The aim of this study was to report a mapping strategy based on different target-aided hearing thresholds to achieve optimal speech recognition and maximize functional outcomes. The safety and efficacy of the mapping strategy were also inspected in the article. METHODS: This prospective repeated measures study enrolled 20 adult CI recipients with postlingual deafness using the MED-EL CI system. Word and sentence discrimination assessment and administration of a questionnaire pertaining to comfort level were conducted at the end of each session. The electrophysiological features of the CI mapping were recorded. RESULTS: The correlation between audiometry results and word and sentence recognition was not high. CIs performed best at an audiometry threshold between 25 and 35 dB. CONCLUSION: CI performance with the best perception relies on a balance between minimizing the hearing threshold and maximizing the dynamic range while maintaining an appropriate comfort level, which was achieved when the target hearing threshold was set at 25-35 dB in this study.

Comparison Benefit between Hydrogen Peroxide and Adrenaline in Tonsillectomy: A Randomized Controlled Study.

This study aimed to further evaluate the benefit of topical hemostasis agents in tonsillectomy. We compared the clinical effects of topical application between hydrogen peroxide and adrenaline in tonsillectomy. Overall, 60 patients (120 tonsils) were prospectively enrolled for tonsillectomy between February 2018 and December 2020. The patients were randomly assigned to either the hydrogen peroxide or adrenaline group. Then, tonsillectomy was performed using hydrogen peroxide as a hemostatic agent on the assigned side, while adrenaline was applied to the other side. All procedures were performed by a surgeon who was blinded to the randomization. The outcome measurements of operation time, intraoperative blood loss, postoperative pain, and hemorrhage events were analyzed. The intraoperative blood loss was significantly lower in the hydrogen peroxide group than in the adrenaline group (9.99 ± 4.51 mL vs. 13.87 ± 6.32 mL; p = 0.0). The median operation time was also significantly lower in the hydrogen peroxide group (8.02 ± 3.59 min vs. 9.22 ± 3.88 min; p = 0.019). Meanwhile, the visual analogue scale (VAS) scores were significantly higher in the hydrogen peroxide group (4.98 ± 1.94 vs. 4.27 ± 1.97; p = 0.001). The topical application of hydrogen peroxide as a hemostatic agent effectively decreases the operation time and intraoperative blood loss. Thus, hydrogen peroxide can be used as a routine hemostatic agent for bleeding control in tonsillectomy.

Bisdemethoxycurcumin-mediated Attenuation of Apoptosis Prevents Gentamicin-induced Ototoxicity in Mouse Cochlear UB/OC-2 Cells.

BACKGROUND/AIM: Gentamicin has been widely prescribed since the last two decades despite its ototoxicity and nephrotoxicity. Bisdemethoxycurcumin (BDMC) is an affordable and safe curcuminoid with medicinal properties. We aimed to understand the effects of BDMC on the gentamicin-induced hair cell damage in mouse cochlear UB/OC-2 cells, in order to elucidate the therapeutic potential of BDMC against gentamicin-induced ototoxicity. MATERIALS AND METHODS: We quantified the cell membrane potential and examined the regulators and cascade proteins in the intrinsic pathway of hair cell apoptosis. Mouse cochlear UB/OC-2 cells were treated with BDMC before exposure to gentamicin. The effects of BDMC on hair cell viability, mitochondrial function, and apoptosis-related proteins were examined by flow cytometry, western blot, and fluorescent staining. RESULTS: Our results revealed that BDMC reversed gentamicin-mediated cycle arrest at the G2/M phase, stabilizing the mitochondrial membrane potential, decreasing cleaved caspase proteins, and successfully reversing hair cell apoptosis. CONCLUSION: BDMC is a potential agent for reducing gentamicin-induced ototoxicity.

Prognostic determinants of hearing outcomes in children with congenital cytomegalovirus infection.

Congenital cytomegalovirus (cCMV) infection is the most prevalent cause of non-genetic sensorineural hearing loss (SNHL) in children. However, the prognostic determinants of SNHL remain unclear. Children with cCMV infection in a tertiary hospital were enrolled. The presence of cCMV-related symptoms at birth, the newborn hearing screening (NHS) results, and the blood viral loads were ascertained. Audiologic outcomes and initial blood viral loads were compared between different groups. Of the 39 children enrolled, 16 developed SNHL. SNHL developed in 60% of children who were initially symptomatic, and in 34.5% of those who were initially asymptomatic with normal hearing or isolated hearing loss, respectively. Failuire in NHS was a reliable tool for early detection of SNHL. The initial viral loads were higher in children who were symptomatic at birth, those who failed NHS, and those who developed SNHL. We observed SNHL deterioration in a patient after CMV DNAemia clearance was achieved, and in another patient with the flare-up of viral load. The presence of cCMV-related symptoms at birth, failure in NHS, and blood viral load might be the prognostic factors for hearing outcomes. Regular audiologic examinations are necessary in all children with cCMV infection even after CMV DNAemia clearance.

2,3,4',5­Tetrahydroxystilbene­2­O­ß­D­glucoside ameliorates gentamicin­induced ototoxicity by modulating autophagy via Sesn2/AMPK/mTOR signaling.

Gentamicin is an important aminoglycoside antibiotic used in the treatment of gram­negative bacterial infections, but nephrotoxicity and ototoxicity reduce its utility. The autophagy pathway is involved in damage of auditory hair cells. With the aim of developing new strategies for attenuating gentamicin ototoxicity, the present study investigated the otoprotective mechanism of 2,3,4',5­tetrahydroxystilbene­2­O­ß­D-glucoside (THSG) in vitro using the mouse cochlear cell line UB/OC­2. MTT assay demonstrated that gentamicin reduced UB/OC­2 cell viability and western blotting showed that gentamicin upregulated autophagy­related proteins, such as Beclin, autophagy related 5 and LC3­II. THSG significantly attenuated gentamicin­induced cytotoxicity, clearly reduced LDH release observed by LDH assay and decreased the expression of autophagy­related proteins. Reverse­transcription­quantitative (RT­q) PCR and western blotting showed that THSG against gentamicin­induced autophagy via suppressing the expression of Sesn2, at both the mRNA and protein level and a possible involvement of AMP­activated protein kinase (AMPK)/mTOR signaling response. Collectively, the present study demonstrated that THSG decreased gentamicin­induced ototoxicity in UB/OC­2 cochlear cells via the autophagic signaling in regulating Sesn2/AMPK/mTOR pathway. These results suggested that THSG might be a new therapeutic agent with the potential to attenuate gentamicin ototoxicity.

Ameliorative effect of taxifolin on gentamicin-induced ototoxicity via down-regulation of apoptotic pathways in mouse cochlear UB/OC-2 cells.

BACKGROUND: Taxifolin is a flavanonol with efficacious cytoprotective properties, such as anti-inflammatory, antioxidant, anticancer, hepatoprotective, and nephroprotective effects. However, the potential protective effects of taxifolin against gentamicin-induced ototoxicity have not been confirmed. In this study, the possible mechanisms underlying the effects of taxifolin on gentamicin-induced death of UB/OC-2 cochlear cells were investigated. METHODS: Mouse cochlear UB/OC-2 cells with or without taxifolin pretreatment were exposed to gentamicin, and the effects on cytotoxicity, reactive oxygen species (ROS) production, mitochondrial permeability transition, and apoptotic marker expression were examined using biochemical techniques, flow cytometry, western blotting, and fluorescent staining. RESULTS: Little or no apparent effect of taxifolin on cell viability was observed at concentrations less than 40 µM. Further investigations showed that gentamicin significantly inhibited cell viability in a concentration-dependent manner. Pretreatment with taxifolin attenuated gentamicin-induced lactate dehydrogenase release, as well as cellular cytotoxicity. In addition, taxifolin significantly prevented gentamicin-induced cell damage by decreasing ROS production, stabilizing mitochondrial membrane potential, and downregulating the mitochondrial pathway of apoptosis. CONCLUSION: In summary, pretreatment with taxifolin is effective for mitigating gentamicin-induced apoptotic cell death mediated by the mitochondrial pathway. Our data suggest that taxifolin provides a new approach to combat gentamicin-induced ototoxicity.

Hearing Features and Cochlear Implantation Outcomes in Patients With Pathogenic MYO15A Variants: a Multicenter Observational Study.

OBJECTIVES: Recessive variants in the MYO15A gene constitute an important cause of sensorineural hearing impairment (SNHI). However, the clinical features of MYO15A-related SNHI have not been systemically investigated. This study aimed to delineate the hearing features and outcomes in patients with pathogenic MYO15A variants. DESIGN: This study recruited 40 patients with biallelic MYO15A variants from 31 unrelated families. The patients were grouped based on the presence of N-terminal domain variants (N variants). The longitudinal audiological data and for those undergoing cochlear implantation, the auditory and speech performance with cochlear implants, were ascertained and compared between patients with different genotypes. RESULTS: At the first audiometric examination, 32 patients (80.0%) presented with severe to profound SNHI. Patients with at least one allele of the N variant exhibited significantly better hearing levels than those with biallelic non-N variants (78.2 ± 23.9 dBHL and 94.7 ± 22.8 dBHL, respectively) (p = 0.033). Progressive SNHI was observed in 82.4% of patients with non-profound SNHI, in whom the average progression rate of hearing loss was 6.3 ± 4.8 dBHL/year irrespective of the genotypes. Most of the 25 patients who underwent cochlear implantation exhibited favorable auditory and speech performances post-implantation. CONCLUSIONS: The hearing features of patients with biallelic pathogenic MYO15A variants are characterized by severe to profound SNHI, rapid hearing progression, and favorable outcomes with cochlear implants. Periodic auditory monitoring is warranted for these patients to enable early intervention.