Testing for genetic and viral etiologies in congenital hearing loss based on a survey of cochlear implant centers: proposed HEARRING group consensus and future directions.

BACKGROUND: In cases of congenital sensorineural hearing loss, testing for genetic etiologies and congenital cytomegalovirus (cCMV) infection have become common practice. AIMS/OBJECTIVES: The purpose of this study is to determine which specific testing methodologies should be used and when. MATERIAL AND METHODS: We surveyed 20 practicing otolaryngologists across eighteen institutions in thirteen countries about their approach to cCMV, GJB2, and wider genetic testing. RESULTS: We found 90% of respondents employ all three tests, either in routine or special cases. cCMV testing is widely used, with 95% of respondents incorporating it into their clinical practice. GJB2 testing was employed by 90%. In cases with negative GJB2 test results, a majority of respondents proceeded to wider genetic screening. Test reimbursement was also examined for each test. For cCMV testing, 63.1% reported reimbursement, 68.4% reported reimbursement for GJB2 variant testing and 52.6% reported reimbursement for wider genetic screening. CONCLUSIONS AND SIGNIFICANCE: A common approach is to perform cCMV and GJB2 testing as the first tests, followed by wider genetic testing. This study offers insight into the prevalence, methodologies, and reimbursement status of these testing methodologies across multiple hearing centers and countries. Current consensus and future directions are described based on the current survey.

Enhanced Cochlear Coverage and Hearing Preservation in High-Frequency Hearing Loss via Electric Acoustic Stimulation with Longer Electrode.

Electric-acoustic stimulation (EAS) is a promising treatment to improve hearing ability in patients with high-frequency hearing loss (HL). In EAS surgeries, shorter electrodes have been preferred to avoid the presence of an electrode covering the residual hearing region. However, our earlier studies showed that EAS with longer electrodes (28 mm) could preserve acoustic hearing. Additionally, we reported that the hearing preservation (HP) scores were independent of the length of the inserted electrodes, consistent with the systematic review. As most EAS patients gradually lose residual hearing over time due to the natural course of HL, in these cases, providing broader cochlear coverage using longer electrodes was beneficial toward better place-pitch matching. In addition to preparing for the deterioration in hearing in the future, EAS with longer electrodes could offer various types of map strategies. Herein, we show the pre-, intra-, and post-procedures for EAS surgery. Appropriate preoperative evaluation, less invasive surgery, flexible lateral-wall electrodes, and steroid administration resulted in good HP following EAS with longer electrodes.

HEARRING group genetic marker study: genetic background of CI patients.

BACKGROUND: While cochlear implantation (CI) and electric acoustic stimulation (EAS) have a positive outcome in most cases, their effectiveness varies depending on the etiology of the hearing loss. Among the various etiologies, genetic factors are the leading cause of hearing loss and may impact CI and EAS outcomes. AIMS/OBJECTIVES: To reveal the genetic background of the hearing loss in CI/EAS patients in each ethnic population, we undertook a multi-center study involving the genetic testing of hearing loss in CI/EAS patients from 10 centers. MATERIAL AND METHODS: Saliva samples and clinical information for the patients and their family members were obtained and next-generation sequencing analysis using a panel carrying 63 deafness genes was then performed. RESULTS: Genetic testing successfully identified the causative gene variants in 54.5% (48/88) of patients with pre-lingual onset hearing loss (onset under 6 years) and in 12% (12/95) of those with late-onset hearing loss (onset at 6 years or more). CONCLUSIONS AND SIGNIFICANCE: We clearly indicated that genetic factors are the most common cause of hearing loss regardless of ethnic background. Saliva-based genetic testing is a useful tool for multi-center studies seeking to clarify the genetic causes of hearing loss in CI or EAS patients between countries separated by distance.

Clinical practice guidelines for the diagnosis and management of acute sensorineural hearing loss.

OBJECTIVE: Acute sensorineural hearing loss represents a spectrum of conditions characterized by sudden onset hearing loss. The "Clinical Practice Guidelines for the Diagnosis and Management of Acute Sensorineural Hearing Loss" were issued as the first clinical practice guidelines in Japan outlining the standard diagnosis and treatment. The purpose of this article is to strengthen the guidelines by adding the scientific evidence including a systematic review of the latest publications, and to widely introduce the current treatment options based on the scientific evidence. METHODS: The clinical practice guidelines were completed by 1) retrospective data analysis (using nationwide survey data), 2) systematic literature review, and 3) selected clinical questions (CQs). Additional systematic review of each disease was performed to strengthen the scientific evidence of the diagnosis and treatment in the guidelines. RESULTS: Based on the nationwide survey results and the systematic literature review summary, the standard diagnosis flowchart and treatment options, including the CQs and recommendations, were determined. CONCLUSION: The guidelines present a summary of the standard approaches for the diagnosis and treatment of acute sensorineural hearing loss. We hope that these guidelines will be used in medical practice and that they will initiate further research.

Generation of an induced pluripotent stem cell line from a late-onset, progressive high frequency hearing loss patient due to mutation in CDH23.

Cadherin 23 (CDH23) is one of the most common genes responsible for hereditary hearing loss; a mutation of CDH23 can cause a wide range of symptoms depending on the variant. In this study, an iPSC line was generated from a patient with late-onset, progressive high frequency hearing loss caused by c.[719C > T];[6085C > T]:p.[P240L];[R2029W] compound heterozygous variants of CDH23. The cells were confirmed to have a normal karyotype, express markers of pluripotency, and have tri-embryonic differentiation potential. This disease-specific iPSC line will further the construction of disease models and the elucidation of the pathophysiology of CDH23 mutations.

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.

Comparison of vestibular function in hereditary hearing loss patients with GJB2, CDH23, and SLC26A4 variants.

To investigate the association between hereditary hearing loss and vestibular function, we compared vestibular function and symptoms among patients with GJB2, SLC26A4, and CDH23 variants. Thirty-nine patients with sensory neural hearing loss (11 males and 28 females) with biallelic pathogenic variants in either GJB2, SLC26A4, or CDH23 were included in this study (13 GJB2, 15 SLC26A4, and 11 CDH23). The patients were examined using caloric testing and cervical and ocular vestibular-evoked myogenic potentials (cVEMP and oVEMP). We also compared vestibular function and symptoms between patients with these gene variants and 78 normal-hearing ears without vestibular symptoms as controls. The frequency of semicircular canal hypofunction in caloric testing was higher in patients with SLC26A4 variants (47%) than in those with GJB2 (0%) and CDH23 variants (27%). According to the cVEMP results, 69% of patients with GJB2 variants had saccular hypofunction, a significantly higher proportion than in those carrying other variants (SLC26A4, 20%; CDH23, 18%). In oVEMP, which reflects utricular function, no difference was observed in the frequency of hypofunction among the three genes (GJB2, 15%; SLC26A4, 40%; and CDH23, 36%). Hence, discernable trends indicate vestibular dysfunction associated with each gene.

Comprehensive Genetic Evaluation in Patients with Special Reference to Late-Onset Sensorineural Hearing Loss.

Hearing loss (HL) is a common and multi-complex etiological deficit that can occur at any age and can be caused by genetic variants, aging, toxic drugs, noise, injury, viral infection, and other factors. Recently, a high incidence of genetic etiologies in congenital HL has been reported, and the usefulness of genetic testing has been widely accepted in congenital-onset or early-onset HL. In contrast, there have been few comprehensive reports on the relationship between late-onset HL and genetic causes. In this study, we performed next-generation sequencing analysis for 91 HL patients mainly consisting of late-onset HL patients. As a result, we identified 23 possibly disease-causing variants from 29 probands, affording a diagnostic rate for this study of 31.9%. The highest diagnostic rate was observed in the congenital/early-onset group (42.9%), followed by the juvenile/young adult-onset group (31.7%), and the middle-aged/aged-onset group (21.4%). The diagnostic ratio decreased with age; however, genetic etiologies were involved to a considerable degree even in late-onset HL. In particular, the responsible gene variants were found in 19 (55.9%) of 34 patients with a familial history and progressive HL. Therefore, this phenotype is considered to be a good candidate for genetic evaluation based on this diagnostic panel.

Epidemiology, aetiology and diagnosis of congenital hearing loss via hearing screening of 153 913 newborns.

BACKGROUND: Congenital hearing loss (HL), one of the most common paediatric chronic conditions, significantly affects speech and language development. Its early diagnosis and medical intervention can be achieved via newborn hearing screening. However, data on the prevalence and aetiology of congenital HL in infants who fail newborn hearing screening are limited. METHODS: The sample population included 153 913 infants who underwent newborn hearing screening, and the prevalence of congenital HL, defined as moderate to profound bilateral HL (BHL) or unilateral HL (UHL) (≥40 dB HL), in one prefecture of Japan was measured to minimize the loss-to-follow-up rate, a common factor affecting the screening procedure. Comprehensive aetiological investigation, including physiology, imaging, genetic tests, and congenital cytomegalovirus screening, was performed on children diagnosed with congenital HL. RESULTS: The calculated prevalence of congenital HL was 1.62 per 1000 newborns (bilateral, 0.84; unilateral, 0.77). More than half of the cases with congenital bilateral or severe to profound UHL showed genetic aetiology or cochlear nerve deficiency (CND), respectively. Approximately 4% and 6% of the cases of congenital BHL and UHL were associated with congenital cytomegalovirus infection and auditory neuropathy spectrum disorder, respectively. CONCLUSIONS: This is an epidemiological and comprehensive aetiological study of congenital HL, as determined via newborn hearing screening according to its severity and laterality, in a large-scale general population of a developed country. Our findings can serve as a reference for optimizing care and intervention options for children with HL and their families.

The prevalence and clinical features of MYO7A-related hearing loss including DFNA11, DFNB2 and USH1B.

The MYO7A gene is known to be responsible for both syndromic hearing loss (Usher syndrome type1B:USH1B) and non-syndromic hearing loss including autosomal dominant and autosomal recessive inheritance (DFNA11, DFNB2). However, the prevalence and detailed clinical features of MYO7A-associated hearing loss across a large population remain unclear. In this study, we conducted next-generation sequencing analysis for a large cohort of 10,042 Japanese hearing loss patients. As a result, 137 patients were identified with MYO7A-associated hearing loss so that the prevalence among Japanese hearing loss patients was 1.36%. We identified 70 disease-causing candidate variants in this study, with 36 of them being novel variants. All variants identified in autosomal dominant cases were missense or in-frame deletion variants. Among the autosomal recessive cases, all patients had at least one missense variant. On the other hand, in patients with Usher syndrome, almost half of the patients carried biallelic null variants (nonsense, splicing, and frameshift variants). Most of the autosomal dominant cases showed late-onset progressive hearing loss. On the other hand, cases with autosomal recessive inheritance or Usher syndrome showed congenital or early-onset hearing loss. The visual symptoms in the Usher syndrome cases developed between age 5-15, and the condition was diagnosed at about 6-15 years of age.

Detailed Clinical Features of PTPRQ-Associated Hearing Loss Identified in a Large Japanese Hearing Loss Cohort.

The PTPRQ gene has been identified as one of the genes responsible for non-syndromic sensorineural hearing loss (SNHL), and assigned as DFNA73 and DFNB84. To date, about 30 causative PTPRQ variants have been reported to cause SNHL. However, the detailed clinical features of PTPRQ-associated hearing loss (HL) remain unclear. In this study, 15,684 patients with SNHL were enrolled and genetic analysis was performed using massively parallel DNA sequencing (MPS) for 63 target deafness genes. We identified 17 possibly disease-causing PTPRQ variants in 13 Japanese patients, with 15 of the 17 variants regarded as novel. The majority of variants identified in this study were loss of function. Patients with PTPRQ-associated HL mostly showed congenital or childhood onset. Their hearing levels at high frequency deteriorated earlier than that at low frequency. The severity of HL progressed from moderate to severe or profound HL. Five patients with profound or severe HL received cochlear implantation, and the postoperative sound field threshold levels and discrimination scores were favorable. These findings will contribute to a greater understanding of the clinical features of PTPRQ-associated HL and may be relevant in clinical practice.

Validation of RNA Extraction Methods and Suitable Reference Genes for Gene Expression Studies in Developing Fetal Human Inner Ear Tissue.

A comprehensive gene expression investigation requires high-quality RNA extraction, in sufficient amounts for real-time quantitative polymerase chain reaction and next-generation sequencing. In this work, we compared different RNA extraction methods and evaluated different reference genes for gene expression studies in the fetal human inner ear. We compared the RNA extracted from formalin-fixed paraffin-embedded tissue with fresh tissue stored at -80 °C in RNAlater solution and validated the expression stability of 12 reference genes (from gestational week 11 to 19). The RNA from fresh tissue in RNAlater resulted in higher amounts and a better quality of RNA than that from the paraffin-embedded tissue. The reference gene evaluation exhibited four stably expressed reference genes (B2M, HPRT1, GAPDH and GUSB). The selected reference genes were then used to examine the effect on the expression outcome of target genes (OTOF and TECTA), which are known to be regulated during inner ear development. The selected reference genes displayed no differences in the expression profile of OTOF and TECTA, which was confirmed by immunostaining. The results underline the importance of the choice of the RNA extraction method and reference genes used in gene expression studies.

Determining optimal cochlear implant electrode array with OTOPLAN.

BACKGROUND: To achieve better speech performance following cochlear implantation (CI), measuring the patient's cochlear duct length (CDL) and determining the appropriate length of the CI array are important. OBJECTIVE: To investigate the CDL in CI patients after using the OTOPLAN software preoperatively and compare the results of angular insertion depth (AID) estimation by OTOPLAN and postoperative radiography. MATERIALS AND METHODS: The study included 105 Japanese CI patients with normal cochleae. We measured the CDL using OTOPLAN and the position of the tip channel of the electrode for each selected electrode array, and estimated the AID using the software. RESULTS: The mean CDL was 35.1 ± 1.6 mm. Preoperatively, the mean estimated AID was 580.3 ± 57.8°. Postoperative radiography revealed a mean AID of 583.0 ± 56.7°, demonstrating a strong linear correlation between the two measurements (R2 = 0.635). CONCLUSION AND SIGNIFICANCE: Our findings revealed that CDL varies widely, which is consistent with previous studies. To achieve better speech perception, surgeons should select the appropriate length of CI electrode array based on the individual's CDL. Preoperative measurement of each CDL by OTOPLAN, which is clinically feasible and comparable to postoperative evaluation, can be used to ensure selection of the appropriate electrode array length.

Otological Features of Patients with Musculocontractural Ehlers-Danlos Syndrome Caused by Pathogenic Variants in CHST14 (mcEDS-CHST14).

Musculocontractural Ehlers-Danlos syndrome (EDS) caused by pathogenic variants in CHST14 (mcEDS-CHST14) is a subtype of EDS characterized by multisystem malformations and progressive fragility-related manifestations. A recent international collaborative study showed that 55% of mcEDS-CHST14 patients had hearing loss (HL), more commonly of the high-frequency type. Here, we report the first systemic investigation of the otological features of patients with this disorder based on the world's largest cohort at Shinshu University Hospital. Nine patients [18 ears; four male and five female patients; mean age, 18 years old (range, 10-28)] underwent comprehensive otological evaluation: audiogram, distortion product otoacoustic emission (DPOAE) test, and tympanometry. The audiogram, available in all 18 ears, showed HL in eight patients (8/9, 89%) and in 14 ears (14/18, 78%): bilateral in six patients (6/9, 67%) and unilateral in two (2/9, 22%); mild in eight ears (8/18, 44%) and moderate in six (6/18, 33%); and high-frequency HL in five (5/18, 28%) and low-frequency HL in five (5/18, 28%). An air-bone gap was detected in one ear (1/18, 6%). DPOAE was available in 13 ears, with the presence of a response in five (5/13, 38%) and the absence in eight (8/13, 62%), including in three ears of normal hearing. Tympanometry results were available in 12 ears: Ad type in nine (9/12, 75%) and As type in one (1/12, 8.3%). Patients with mcEDS-CHST14 had a high prevalence of HL, typically sensorineural and bilateral, with mild to moderate severity, of high-frequency or low-frequency type, and sometimes with no DPOAE response. The pathophysiology underlying HL might be complex, presumably related to alterations of the tectorial membrane and/or the basilar membrane of Corti associated with disorganized collagen fibril networks. Regular and careful check-ups of hearing using multiple modalities are recommended for mcEDS-CHST14 patients.

Generation and characterization of a human iPSC line (JUFMDOi007-A) from a patient with Usher syndrome due to mutation in USH2A.

Usher syndrome type 2A (USH2A) gene mutations have been identified as the most frequent genetic causes of hereditary deafness in Usher syndrome, and an effective treatment has yet to be established. The encoded protein, Usherin, is essential for the ankle link associated with extracellular connections between the stereocilia of inner ear hair cells. We report the generation of a patient-derived USH2A iPSC line with compound mutations c.1907_1912ATGTTT > TCACAG (p.D636V + V637T + C638G) and c.8328_8329delAA (p.L2276fs*12). The iPSC showed the expression of pluripotency markers, the ability to differentiate into three germ layers in vitro, and USH2A mutations with normal karyotype.

The relationship between preoperative factors and the pattern of longitudinal improvement in speech perception following cochlear implantation.

BACKGROUND: Many studies have discussed the factors influencing hearing outcomes after cochlear implantation, but few have addressed improvements in speech perception for these patients over time. OBJECTIVE: To investigate the relationship between preoperative factors and the pattern of longitudinal improvement in speech perception following cochlear implantation (CI). MATERIALS AND METHODS: This study enrolled 83 patients (96 ears) who underwent CI at Shinshu University Hospital. The patients were assessed up to 12 months after CI by a monosyllable test, and showed either delayed improvement (DI), early improvement (EI), or stable improvement (SI) when compared with their preoperative score. Eight preoperative variables were also examined for their effects on speech perception over time. RESULTS: The DI, EI, SI groups comprised 35.4%, 43.8%, and 20.8% of all patients, respectively. Patients in the DI group were older at surgery than those in the EI and SI groups, and their onset age were also older than that in the SI group. No other preoperative variables showed significant differences across the three groups. CONCLUSIONS AND SIGNIFICANCE: Our findings revealed that age at implantation and age at onset of hearing loss significantly affected the improvement pattern of speech perception. Age may be useful in predicting recovery of speech perception after CI.

Sound localization in patients with idiopathic sudden hearing loss.

BACKGROUND: Patients with unilateral hearing loss have difficulty localizing sound. Severe-to-profound unilateral hearing loss is most commonly caused by idiopathic sudden sensorineural hearing loss (SSNHL). AIMS/OBJECTIVES: To assess the sound localization ability of patients with idiopathic unilateral SSNHL and examine the factors affecting the results. MATERIAL AND METHODS: We retrospectively enrolled 141 patients with idiopathic unilateral SSNHL. The assessment stimuli were speech-shaped noise from one of the nine loudspeakers in a 180° arc. Multiple regression analysis was used to examine the factors that affected sound localization ability. RESULTS: There was a strong correlation between the hearing level on the affected side post-treatment and the deviation score as the index of sound localization ability. The results of the multiple regression analysis suggested that sound localization may be partially affected by hearing level on the unaffected side and age. CONCLUSIONS AND SIGNIFICANCE: The results showed that sound localization ability decreased in idiopathic SSNHL patients with severe-to-profound hearing loss post-treatment. This study provides important data for future interventions for unilateral hearing loss, including cochlear implants.

Estimated number and prevalence of patients with delayed endolymphatic hydrops in Japan: a nationwide survey.

BACKGROUND: Delayed endolymphatic hydrops (DEH) is a rare disease, and the actual number of patients in Japan remains unknown. OBJECTIVE: To investigate the number and prevalence of patients with DEH in Japan. METHODS: In total, 781 departments of otolaryngology in Japan were selected for survey by stratified random sampling according to the total number of hospital beds. We sent questionnaires to the target departments and collected data regarding the number of patients with DEH who visited those departments in 2019. RESULTS: The overall response rate was 68.0% (531 departments). The estimate number of patients with DEH in Japan was 962, and the prevalence was calculated to be 0.8 per 100,000 population. CONCLUSION: Patients with DEH were extremely rare in Japan. SIGNIFICANCE: This may be the first nationwide epidemiological study on the number and prevalence of patients with DEH in Japan or in the world.

Minimally Traumatic Cochlear Implant Surgery: Expert Opinion in 2010 and 2020.

This study aimed to discover expert opinion on the surgical techniques and materials most likely to achieve maximum postoperative residual hearing preservation in cochlear implant (CI) surgery and to determine how these opinions have changed since 2010. A previously published questionnaire used in a study published in 2010 was adapted and expanded. The questionnaire was distributed to an international group of experienced CI surgeons. Present results were compared, via descriptive statistics, to those from the 2010 survey. Eighteen surgeons completed the questionnaire. Respondents clearly favored the following: round window insertion, slow array insertion, and the peri- and postoperative use of systematic antibiotics. Insertion depth was regarded as important, and electrode arrays less likely to induce trauma were preferred. The usefulness of dedicated soft-surgery training was also recognized. A lack of agreement was found on whether the middle ear cavity should be flushed with a non-aminoglycoside antibiotic solution or whether a sheath or insertion tube should be used to avoid contaminating the array with blood or bone dust. In conclusion, this paper demonstrates how beliefs about CI soft surgery have changed since 2010 and shows areas of current consensus and disagreement.