Variants in CDH23 cause a broad spectrum of hearing loss: from non-syndromic to syndromic hearing loss as well as from congenital to age-related hearing loss.

Variants in the CDH23 gene are known to be responsible for both syndromic hearing loss (Usher syndrome type ID: USH1D) and non-syndromic hearing loss (DFNB12). Our series of studies demonstrated that CDH23 variants cause a broad range of phenotypes of non-syndromic hearing loss (DFNB12); from congenital profound hearing loss to late-onset high-frequency-involved progressive hearing loss. In this study, based on the genetic and clinical data from more than 10,000 patients, the mutational spectrum, clinical characteristics and genotype/phenotype correlations were evaluated. The present results reconfirmed that the variants in CDH23 are an important cause of non-syndromic sensorineural hearing loss. In addition, we showed that the mutational spectrum in the Japanese population, which is probably representative of the East Asian population in general, as well as frequent CDH23 variants that might be due to some founder effects. The present study demonstrated CDH23 variants cause a broad range of phenotypes, from non-syndromic to syndromic hearing loss as well as from congenital to age-related hearing loss. Genotype (variant combinations) and phenotype (association with retinal pigmentosa, onset age) are shown to be well correlated and are thought to be related to the residual function defined by the CDH23 variants.

Frequency of Usher syndrome type 1 in deaf children by massively parallel DNA sequencing.

Usher syndrome type 1 (USH1) is the most severe of the three USH subtypes due to its profound hearing loss, absent vestibular response and retinitis pigmentosa appearing at a prepubescent age. Six causative genes have been identified for USH1, making early diagnosis and therapy possible through DNA testing. Targeted exon sequencing of selected genes using massively parallel DNA sequencing (MPS) technology enables clinicians to systematically tackle previously intractable monogenic disorders and improve molecular diagnosis. Using MPS along with direct sequence analysis, we screened 227 unrelated non-syndromic deaf children and detected recessive mutations in USH1 causative genes in five patients (2.2%): three patients harbored MYO7A mutations and one each carried CDH23 or PCDH15 mutations. As indicated by an earlier genotype-phenotype correlation study of the CDH23 and PCDH15 genes, we considered the latter two patients to have USH1. Based on clinical findings, it was also highly likely that one patient with MYO7A mutations possessed USH1 due to a late onset age of walking. This first report describing the frequency (1.3-2.2%) of USH1 among non-syndromic deaf children highlights the importance of comprehensive genetic testing for early disease diagnosis.

Towards a Unified Testing Framework for Single-Sided Deafness Studies: A Consensus Paper.

BACKGROUND: While hearing aids for a contralateral routing of signals (CROS-HA) and bone conduction devices have been the traditional treatment for single-sided deafness (SSD) and asymmetric hearing loss (AHL), in recent years, cochlear implants (CIs) have increasingly become a viable treatment choice, particularly in countries where regulatory approval and reimbursement schemes are in place. Part of the reason for this shift is that the CI is the only device capable of restoring bilateral input to the auditory system and hence of possibly reinstating binaural hearing. Although several studies have independently shown that the CI is a safe and effective treatment for SSD and AHL, clinical outcome measures in those studies and across CI centers vary greatly. Only with a consistent use of defined and agreed-upon outcome measures across centers can high-level evidence be generated to assess the safety and efficacy of CIs and alternative treatments in recipients with SSD and AHL. METHODS: This paper presents a comparative study design and minimum outcome measures for the assessment of current treatment options in patients with SSD/AHL. The protocol was developed, discussed, and eventually agreed upon by expert panels that convened at the 2015 APSCI conference in Beijing, China, and at the CI 2016 conference in Toronto, Canada. RESULTS: A longitudinal study design comparing CROS-HA, BCD, and CI treatments is proposed. The recommended outcome measures include (1) speech in noise testing, using the same set of 3 spatial configurations to compare binaural benefits such as summation, squelch, and head shadow across devices; (2) localization testing, using stimuli that rove in both level and spectral content; (3) questionnaires to collect quality of life measures and the frequency of device use; and (4) questionnaires for assessing the impact of tinnitus before and after treatment, if applicable. CONCLUSION: A protocol for the assessment of treatment options and outcomes in recipients with SSD and AHL is presented. The proposed set of minimum outcome measures aims at harmonizing assessment methods across centers and thus at generating a growing body of high-level evidence for those treatment options.

Massively parallel DNA sequencing successfully identified seven families with deafness-associated MYO6 mutations: the mutational spectrum and clinical characteristics.

OBJECTIVES: To elucidate the involvement of MYO6 mutations, known to be responsible for DFNA22/DFNB37, in Japanese hearing loss patients through the use of genetic analysis. METHODS: Genomic variations responsible for hearing loss were identified by massively parallel DNA sequencing (MPS) of 63 target candidate genes in 1120 Japanese hearing loss patients, and the detailed clinical features for the patients with MYO6 mutations were collected and analyzed. RESULTS: Four mutations were successfully found in 7 families exhibiting autosomal dominant inheritance. All of the patients showed progressive hearing loss, but hearing type and onset age varied. Further, none of the affected patients showed any associated symptoms, such as hypertrophic cardiomyopathy or retinitis pigmentosa. CONCLUSIONS: MPS is powerful tool for the identification of rare causative deafness gene mutations, such as MYO6. The clinical characteristics noted in the present study not only confirmed the findings of previous reports but provided important new clinical information.

Germinal mosaicism in a family with BO syndrome.

OBJECTIVES: To clarify the existence of germinal mosaicism, we performed a genetic analysis of 2 siblings identified with an EYA1 mutation associated with branchiooto (BO) syndrome but who were born from normal parents. METHODS: Detailed data from the 2 affected siblings were collected for clinical diagnosis, with haplotype analysis also performed to prove germinal mosaicism. RESULTS: The 2 sisters showed characteristic clinical features of BO syndrome (middle and inner ear anomalies, microtia, and auditory canal stenosis/atresia). Haplotype analysis confirmed the genetic relationship between the affected sisters and their parents. The younger sister with auditory canal atresia received a bone-anchored hearing aid (Baha), a transcutaneous bone conduction hearing device, resulting in a good hearing outcome. CONCLUSIONS: Based on the results of haplotype analysis, we proved that the BO syndrome in these cases was caused by germinal mosaicism of the EYA1 gene in either the mother or father. We also demonstrated that the bone-conduction hearing implant is a good option for BO patients with complex outer, middle, and inner ear anomalies.

Mutational spectrum and clinical features of patients with ACTG1 mutations identified by massively parallel DNA sequencing.

OBJECTIVES: ACTG1 has been reported to be a causative gene for autosomal dominant sensorineural hearing loss, DFNA20/26. In this study we sought to clarify the detailed mutational spectrum, clinical features, and genotype-phenotype correlations. METHODS: Massively parallel DNA sequencing (MPS) of 63 target candidate genes was used to screen 1120 Japanese hearing loss patients. RESULTS: MPS screening successfully identified 4 ACTG1 mutations in 5 families. The majority of patients showed high frequency-involved progressive hearing loss, with the age of onset mostly in the first or second decade. One patient received electric acoustic stimulation (EAS), which showed a good outcome. CONCLUSIONS: Target exon-sequencing using MPS was proven to be a powerful new clinical diagnostic tool for the identification of rare causative genes such as ACTG1. The present clinical findings not only confirmed those previous reports but also provided important new clinical information.

The patients associated with TMPRSS3 mutations are good candidates for electric acoustic stimulation.

OBJECTIVES: To clarify the frequency of TMPRSS3 mutations in the hearing loss population, genetic analysis was performed, and detailed clinical characteristics were collected. Optical intervention for patients with TMPRSS3 mutations was also discussed. METHODS: Massively parallel DNA sequencing (MPS) was applied for the target exon-sequencing of 63 deafness genes in a population of 1120 Japanese hearing loss patients. RESULTS: Hearing loss in 5 patients was found to be caused by compound heterozygous TMPRSS3 mutations, and their detailed clinical features were collected and analyzed. Typically, all of the patients showed ski slope type audiograms and progressive hearing loss. Three of the 5 patients received electric acoustic stimulation (EAS), which showed good results. Further, the onset age was found to vary, and there were some correlations between genotype and phenotype (onset age). CONCLUSIONS: MPS is a powerful tool for the identification of rare causative deafness genes, such as TMPRSS3. The present clinical characteristics not only confirmed the findings from previous studies but also provided clinical evidence that EAS is beneficial for patients possessing TMPRSS3 mutations.

Detailed hearing and vestibular profiles in the patients with COCH mutations.

OBJECTIVES: To evaluate the clinical features of Japanese DFNA9 families with mutations of the COCH gene. METHODS: Mutation screening was performed using targeted next-generation sequencing (NGS) for 63 previously reported deafness genes. The progression of hearing loss and vestibular dysfunction were evaluated by pure-tone audiometry, caloric testing, cVEMP, and computed dynamic posturography. RESULTS: We detected 1 reported mutation of p.G88E and 2 novel mutations of p.I372T and p.C542R. The patients with the novel mutations of p.I372T and p.C542R within the vWFA2 domain showed early onset progressive hearing loss, and the patients with the p.G88E mutation showed late onset hearing loss and acute hearing deterioration over a short period. Vestibular symptoms were reported in the patients with p.G88E and p.C542R. Vestibular testing was performed for the family with the p.G88E mutation. Severe vestibular dysfunction was observed in the proband, and the proband's son showed unilateral semicircular canal dysfunction with mild hearing loss. CONCLUSIONS: Targeted exon resequencing of selected genes using NGS successfully identified mutations in the relatively rare deafness gene, COCH, in the Japanese population. The phenotype is compatible with that described in previous reports. Additional supporting evidence concerning progressive hearing loss and deterioration of vestibular function was obtained from our study.

Mutations in the MYO15A gene are a significant cause of nonsyndromic hearing loss: massively parallel DNA sequencing-based analysis.

OBJECTIVES: Screening for MYO15A mutations was carried out using a large cohort to clarify the frequency and clinical characteristics of patients with MYO15A (DFNB3) mutations in a hearing loss population. METHODS: Genetic analysis of 63 previously reported deafness genes based on massively parallel DNA sequencing (MPS) in 1120 Japanese hearing loss patients from 53 otorhinolaryngology departments was performed. Detailed clinical features of the patients with MYO15A mutations were then collected and analyzed. RESULTS: Eleven patients from 10 families were found to have compound heterozygosity for MYO15A. Audiograms showed profound or high frequency hearing loss, with some patients showing progressive hearing loss. Age at onset was found to vary from 0 to 14 years, which seemed to be associated with the mutation. Four children underwent bilateral cochlear implantation for congenital hearing loss, with all showing good results. CONCLUSION: Mutations in the MYO15A gene are a notable cause of nonsyndromic hearing loss. MPS technology successfully detected mutations in relatively rare deafness genes such as MYO15A.

Gene expression profiles of the cochlea and vestibular endorgans: localization and function of genes causing deafness.

OBJECTIVES: We sought to elucidate the gene expression profiles of the causative genes as well as the localization of the encoded proteins involved in hereditary hearing loss. METHODS: Relevant articles (as of September 2014) were searched in PubMed databases, and the gene symbols of the genes reported to be associated with deafness were located on the Hereditary Hearing Loss Homepage using localization, expression, and distribution as keywords. RESULTS: Our review of the literature allowed us to systematize the gene expression profiles for genetic deafness in the inner ear, clarifying the unique functions and specific expression patterns of these genes in the cochlea and vestibular endorgans. CONCLUSIONS: The coordinated actions of various encoded molecules are essential for the normal development and maintenance of auditory and vestibular function.

Mutation spectrum and genotype-phenotype correlation of hearing loss patients caused by SLC26A4 mutations in the Japanese: a large cohort study.

Mutations in SLC26A4 cause a broad phenotypic spectrum, from typical Pendred syndrome to nonsyndromic hearing loss associated with enlarged vestibular aqueduct. Identification of these mutations is important for accurate diagnosis, proper medical management and appropriate genetic counseling and requires updated information regarding spectrum, clinical characteristics and genotype-phenotype correlations, based on a large cohort. In 100 patients with bilateral enlarged vestibular aqueduct among 1511 Japanese hearing loss probands registered in our gene bank, goiter data were available for 79, of whom 15 had Pendred syndrome and 64 had nonsyndromic hearing loss. We clarified the mutation spectrum for the SLC26A4 mutations and also summarized hearing levels, progression, fluctuation and existence of genotype-phenotype correlation. SLC26A4 mutations were identified in 82 of the 100 patients (82.0%). Of the Pendred syndrome patients, 93% (14/15) were carriers, as were 77% (49/64) of the nonsyndromic hearing loss patients. Clinical characteristics of patients with SLC26A4 mutations were congenital, fluctuating and progressive hearing loss usually associated with vertigo and/or goiter. We found no genotype-phenotype correlations, indicating that, unlike in the case of GJB2 mutations, the phenotype cannot be predicted from the genotype. Our mutation analysis confirmed the importance of mutations in the SLC26A4 gene among hearing loss patients with enlarged vestibular aqueduct and revealed the mutation spectrum, essential information when performing genetic testing.

Etiology of hearing loss affects auditory skill development and vocabulary development in pediatric cochlear implantation cases.

BACKGROUND: Cochlear implantation (CI) is an effective treatment for severe-to-profound hearing loss patients and is currently used as the standard therapeutic option worldwide. However, the outcomes of CI vary among patients. AIMS/OBJECTIVES: This study aimed to clarify the clinical features for each etiological group as well as the effects of etiology on CI outcomes. MATERIALS AND METHODS: We collected clinical information for 308 pediatric cochlear implant cases, including the etiology, hearing thresholds, age at CI, early auditory skill development, total development, monosyllable perception, speech intelligibility and vocabulary development in school age, and compared them for each etiology group. RESULTS: Among the 308 CI children registered for this survey, the most common etiology of hearing loss was genetic causes. The genetic etiology group showed the most favorable development after CI followed by the unknown etiology group, syndromic hearing loss group, congenital CMV infection group, inner ear malformation group, and cochlear nerve deficiency group. CONCLUSIONS AND SIGNIFICANCE: Our results clearly indicated that the etiology of HL affects not only early auditory skill development, but also vocabulary development in school age. The results of the present study will aid in more appropriate CI outcome assessment and in more appropriate intervention or habilitation programs.

Genetic testing has the potential to impact hearing preservation following cochlear implantation.

Background: Recent advances in less-invasive surgery and electrode design allow for a high degree of hearing preservation (HP) after cochlear implantation (CI), although residual hearing still deteriorates in some patients. To date, the factors predictive of preserving residual hearing remain a controversial topic.Objective: The aim of this study was to investigate the predictive factors, including the etiology of hearing loss (HL) as a patient-related factor, influencing residual HP after CI.Methods: Forty-four patients (50 ears, 41 families) with residual acoustic hearing who underwent CI were included. Auditory thresholds before and at 6 months after initial activation were measured. Genetic testing was performed to identify the responsible genes for HL.Results: We identified the cause of HL in 21 families (51.2%). HP was marginally correlated with age at implantation, while it was independent of pre-operative low-frequency hearing thresholds, cochlear duct length, and electrode length. We found that patients who had pathogenic variants in the CDH23, MYO7A, or MYO15A gene showed statistically better HP scores compared with patients with HL due to other causes (p = .002).Conclusions: Identification of the etiology of HL using genetic testing is likely to facilitate the prediction of HP after implant surgery.

Cochlear Implantation From the Perspective of Genetic Background.

While cochlear implantation (CI) technology has greatly improved over the past 40 years, one aspect of CI that continues to pose difficulties is the variability of outcomes due to numerous factors involved in postimplantation performance. The electric acoustic stimulation (EAS) system has expanded indications for CI to include patients with residual hearing, and is currently becoming a standard therapy for these patients. Genetic disorders are known to be the most common cause of congenital/early-onset sensorineural hearing loss, and are also involved in a considerable proportion of cases of late-onset hearing loss. There has been a great deal of progress in the identification of deafness genes over the last two decades. Currently, more than 100 genes have been reported to be associated with non-syndromic hearing loss. Patients possessing a variety of deafness gene mutations have achieved satisfactory auditory performance after CI/EAS, suggesting that identification of the genetic background facilitates prediction of post-CI/EAS performance. When the intra-cochlear etiology is associated with a specific genetic background, there is a potential for good CI performance. Thus, it is essential to determine which region of the cochlea is affected by identifying the responsible genes. This review summarizes the genetic background of the patients receiving CI/EAS, and introduces detailed clinical data and CI/EAS outcomes in representative examples. Anat Rec, 303:563-593, 2020. © 2020 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.

Clinical Characteristics and In Vitro Analysis of MYO6 Variants Causing Late-Onset Progressive Hearing Loss.

MYO6 is known as a genetic cause of autosomal dominant and autosomal recessive inherited hearing loss. In this study, to clarify the frequency and clinical characteristics of hearing loss caused by MYO6 gene mutations, a large-scale genetic analysis of Japanese patients with hearing loss was performed. By means of massively parallel DNA sequencing (MPS) using next-generation sequencing for 8074 Japanese families, we found 27 MYO6 variants in 33 families, 22 of which are novel. In total, 2.40% of autosomal dominant sensorineural hearing loss (ADSNHL) in families in this study (32 out of 1336) was found to be caused by MYO6 mutations. The present study clarified that most cases showed juvenile-onset progressive hearing loss and their hearing deteriorated markedly after 40 years of age. The estimated hearing deterioration was found to be 0.57 dB per year; when restricted to change after 40 years of age, the deterioration speed was accelerated to 1.07 dB per year. To obtain supportive evidence for pathogenicity, variants identified in the patients were introduced to MYO6 cDNA by site-directed mutagenesis and overexpressed in epithelial cells. They were then assessed for their effects on espin1-induced microvilli formation. Cells with wildtype myosin 6 and espin1 co-expressed created long microvilli, while co-expression with mutant constructs resulted in severely shortened microvilli. In conclusion, the present data clearly showed that MYO6 is one of the genes to keep in mind with regard to ADSNHL, and the molecular characteristics of the identified gene variants suggest that a possible pathology seems to result from malformed stereocilia of the cochlear hair cells.

Comprehensive analysis of syndromic hearing loss patients in Japan.

More than 400 syndromes associated with hearing loss and other symptoms have been described, corresponding to 30% of cases of hereditary hearing loss. In this study we aimed to clarify the mutation spectrum of syndromic hearing loss patients in Japan by using next-generation sequencing analysis with a multiple syndromic targeted resequencing panel (36 target genes). We analyzed single nucleotide variants, small insertions, deletions and copy number variations in the target genes. We enrolled 140 patients with any of 14 syndromes (BOR syndrome, Waardenburg syndrome, osteogenesis imperfecta, spondyloepiphyseal dysplasia congenita, Stickler syndrome, CHARGE syndrome, Jervell and Lange-Nielsen syndrome, Pendred syndrome, Klippel-Feil syndrome, Alport syndrome, Norrie disease, Treacher-Collins syndrome, Perrault syndrome and auditory neuropathy with optic atrophy) and identified the causative variants in 56% of the patients. This analysis could identify the causative variants in syndromic hearing loss patients in a short time with a high diagnostic rate. In addition, it was useful for the analysis of the cases who only partially fulfilled the diagnostic criteria.

Feasibility of hearing preservation for residual hearing with longer cochlear implant electrodes.

BACKGROUND: Hearing preservation is thought to be achievable following atraumatic surgery with thin cochlear implant electrodes; therefore, the surgical approach and implant electrode design are crucial considerations. OBJECTIVE: To assess the feasibility of hearing preservation with long electrodes for patients meeting the criteria for conventional cochlear implantation. METHODS: One hundred and two patients (132 ears) who underwent cochlear implant surgery were analyzed. Inclusion criteria included measurable residual hearing in the low frequency before implantation and not meeting the criteria for electric acoustic stimulation (EAS). RESULTS: Of the 18 patients with residual hearing in the low frequency enrolled, 17 subjects (94.4%) retained low frequency hearing. A younger age at surgery tended to contribute to better hearing preservation than that observed in older patients. There was no clear trend regarding the influence of insertion depth angle of the electrode on hearing preservation. CONCLUSION: It is possible to achieve hearing preservation in the lower frequency by the use of longer electrodes. This study underscores the importance of atraumatic surgery, even for patients with only limited residual hearing, and longer electrodes should be adopted for EAS.

WFS1 mutation screening in a large series of Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis.

A heterozygous mutation in the Wolfram syndrome type 1 gene (WFS1) causes autosomal dominant nonsyndromic hereditary hearing loss, DFNA6/14/38, or Wolfram-like syndrome. To date, more than 40 different mutations have been reported to be responsible for DFNA6/14/38. In the present study, WFS1 variants were screened in a large series of Japanese hearing loss (HL) patients to clarify the prevalence and clinical characteristics of DFNA6/14/38 and Wolfram-like syndrome. Massively parallel DNA sequencing of 68 target genes was performed in 2,549 unrelated Japanese HL patients to identify genomic variations responsible for HL. The detailed clinical features in patients with WFS1 variants were collected from medical charts and analyzed. We successfully identified 13 WFS1 variants in 19 probands: eight of the 13 variants were previously reported mutations, including three mutations (p.A684V, p.K836N, and p.E864K) known to cause Wolfram-like syndrome, and five were novel mutations. Variants were detected in 15 probands (2.5%) in 602 families with presumably autosomal dominant or mitochondrial HL, and in four probands (0.7%) in 559 sporadic cases; however, no variants were detected in the other 1,388 probands with autosomal recessive or unknown family history. Among the 30 individuals possessing variants, marked variations were observed in the onset of HL as well as in the presence of progressive HL and tinnitus. Vestibular symptoms, which had been rarely reported, were present in 7 out of 30 (23%) of the affected individuals. The most prevalent audiometric configuration was low-frequency type; however, some individuals had high-frequency HL. Haplotype analysis in three mutations (p.A716T, p.K836T, and p.E864K) suggested that the mutations occurred at these mutation hot spots. The present study provided new insights into the audiovestibular phenotypes in patients with WFS1 mutations.

Long-term results of hearing preservation cochlear implant surgery in patients with residual low frequency hearing.

CONCLUSION: Differences were found between patients with stable hearing and those with progressive hearing loss in the lower frequencies with respect to the rate of progression in the contralateral ear. It is suggested that the electric acoustic stimulation (EAS) can provide improvement in hearing ability over the long-term if residual hearing might be lost to some extent. OBJECTIVE: To evaluate the long-term threshold changes in the low frequency hearing of the implanted ear as compared with the non-implanted ear, and the hearing abilities with EAS along with the extent of residual hearing. METHODS: Seventeen individuals were enrolled and received the EAS implant with a 24-mm FLEXeas electrode array. Hearing thresholds and speech perception were measured pre- and post-operatively for 1-5 years. Post-operative hearing preservation (HP) rates were calculated using the preservation numerical scale. RESULTS: The average linear regression coefficient for the decline in hearing preservation score was -6.9 for the implanted ear and the patients were subsequently categorized into two groups: those with better than average, stable hearing; and those with worse than average, progressive hearing loss. EAS showed better results than electric stimulation alone, in spite of an absence of speech perception with acoustic stimulation.

POU4F3 mutation screening in Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis identified novel variants associated with autosomal dominant hearing loss.

A variant in a transcription factor gene, POU4F3, is responsible for autosomal dominant nonsyndromic hereditary hearing loss, DFNA15. To date, 14 variants, including a whole deletion of POU4F3, have been reported to cause HL in various ethnic groups. In the present study, genetic screening for POU4F3 variants was carried out for a large series of Japanese hearing loss (HL) patients to clarify the prevalence and clinical characteristics of DFNA15 in the Japanese population. Massively parallel DNA sequencing of 68 target candidate genes was utilized in 2,549 unrelated Japanese HL patients (probands) to identify genomic variations responsible for HL. The detailed clinical features in patients with POU4F3 variants were collected from medical charts and analyzed. Novel 12 POU4F3 likely pathogenic variants (six missense variants, three frameshift variants, and three nonsense variants) were successfully identified in 15 probands (2.5%) among 602 families exhibiting autosomal dominant HL, whereas no variants were detected in the other 1,947 probands with autosomal recessive or inheritance pattern unknown HL. To obtain the audiovestibular configuration of the patients harboring POU4F3 variants, we collected audiograms and vestibular symptoms of the probands and their affected family members. Audiovestibular phenotypes in a total of 24 individuals from the 15 families possessing variants were characterized by progressive HL, with a large variation in the onset age and severity with or without vestibular symptoms observed. Pure-tone audiograms indicated the most prevalent configuration as mid-frequency HL type followed by high-frequency HL type, with asymmetry observed in approximately 20% of affected individuals. Analysis of the relationship between age and pure-tone average suggested that individuals with truncating variants showed earlier onset and slower progression of HL than did those with non-truncating variants. The present study showed that variants in POU4F3 were a common cause of autosomal dominant HL.