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.

Unusual phenotype in 35delG mutation: a case report.

BACKGROUND: Mutations in the GJB2 gene, which encodes the protein connexin 26 and is involved in inner ear homeostasis, are identified in approximately 50% of patients with autosomal recessive nonsyndromic hearing loss, making it one of the primary causes of prelingual nonsyndromic hearing loss in various populations. The 35delG mutation, one of the most common mutations of the GJB2 gene, usually causes prelingual, bilateral mild to profound, nonprogressive sensorineural hearing loss. CASE PRESENTATION: We present an unusual case of an 18-year-old Turkish female with heterozygous 35delG mutation and postlingual, profound-sloping, progressive and fluctuating unilateral sensorineural hearing loss. The phenotype is different from the usual findings. CONCLUSIONS: The 35delG mutation causing hearing loss may not always be reflected in the phenotype as expected and therefore may have different audiologic manifestations.

Updates on Genetic Hearing Loss: From Diagnosis to Targeted Therapies.

Sensorineural hearing loss (SNHL) is the most common sensory disorder, with a high Mendelian genetic contribution. Considering the genotypic and phenotypic heterogeneity of SNHL, the advent of next-generation sequencing technologies has revolutionized knowledge on its genomic architecture. Nonetheless, the conventional application of panel and exome sequencing in real-world practice is being challenged by the emerging need to explore the diagnostic capability of whole-genome sequencing, which enables the detection of both noncoding and structural variations. Small molecules and gene therapies represent good examples of how breakthroughs in genetic understanding can be translated into targeted therapies for SNHL. For example, targeted small molecules have been used to ameliorate autoinflammatory hearing loss caused by gain-of-function variants of NLRP3 and inner ear proteinopathy with OSBPL2 variants underlying dysfunctional autophagy. Strikingly, the successful outcomes of the first-in-human trial of OTOF gene therapy highlighted its potential in the treatment of various forms of genetic hearing loss. clustered regularly interspaced short palindromic repeats (CRISPR)-based technologies are currently being developed for site-specific genome editing to treat human genetic disorders. These advancements have led to an era of genotype- and mechanism-based precision medicine in SNHL practice.

Diagnóstico genético de la hipoacusia neurosensorial infantil / Genetic diagnosis of childhood sensorineural hearing loss

Introducción: La hipoacusia neurosensorial (HNS) congénita o de inicio precoz es una de las enfermedades hereditarias más frecuentes en nuestro medio y es la deficiencia sensorial más frecuente. Es importante realizar un estudio etiológico de la hipoacusia y el estudio genético mediante la secuenciación de nueva generación (NGS) es la prueba con mayor rendimiento diagnóstico. Nuestro estudio muestra los resultados genéticos obtenidos en una serie de pacientes con HNS congénita/de inicio precoz bilateral. Material y método: Se incluyeron 105 niños diagnosticados de HNS bilateral a los que se les realizó un estudio genético entre los años 2019 y 2022. El estudio genético consistió en una secuenciación masiva del exoma completo, filtrando el análisis para los genes incluidos en un panel virtual de hipoacusia con 244 genes. Resultados: Se obtuvo un diagnóstico genético en 48% (50/105) de los pacientes. Se detectaron variantes patogénicas y probablemente patogénicas en 26 genes diferentes, siendo los genes más frecuentemente afectados el gen GJB2, USH2A y STRC. De las variantes detectadas 52% (26/50) se asociaron a una hipoacusia no sindrómica, 40% (20/50) una hipoacusia sindrómica y 8% restante (4/50) se podían asociar tanto a una hipoacusia sindrómica como no sindrómica. Conclusiones: El estudio genético constituye una parte fundamental del diagnóstico etiológico de la HNS bilateral. Nuestra serie muestra que el estudio genético de la hipoacusia mediante NGS tiene un alto rendimiento diagnóstico y nos proporciona información de gran utilidad en la práctica clínica.(AU)

Introduction: Congenital/early-onset sensorineural hearing loss (SNHL) is one of the most common hereditary disorders in our environment. There is increasing awareness of the importance of an etiologic diagnosis, and genetic testing with next-generation sequencing (NGS) has the highest diagnostic yield. Our study shows the genetic results obtained in a cohort of patients with bilateral congenital/early-onset SNHL. Materials and methods: We included 105 children with bilateral SNHL that received genetic testing between 2019 and 2022. Genetic tests were performed with whole exome sequencing, analyzing genes related to hearing loss (virtual panel with 244 genes). Results: 48% (50/105) of patients were genetically diagnosed. We identified pathogenic and likely pathogenic variants in 26 different genes, and the most frequently mutated genes were GJB2, USH2A and STRC. 52% (26/50) of variants identified produced non-syndromic hearing loss, 40% (20/50) produced syndromic hearing loss, and the resting 8% (4/50) could produce both non-syndromic and syndromic hearing loss. Conclusions: Genetic testing plays a vital role in the etiologic diagnosis of bilateral SNHL. Our cohort shows that genetic testing with NGS has a high diagnostic yield and can provide useful information for the clinical workup of patients.(AU)

Audiological Phenotypes of Connexin Gene Mutation Patterns: A Glance at Different GJB2/GJB6 Gene Mutation Profiles.

GJB2 mutations are the most common cause of autosomal-recessive non-syndromic sensorineural hearing loss (SNHL). The available evidence shows large phenotypic variability across different genotypes and allelic variants. The aim of this study was to investigate the clinical and audiological features of a cohort of subjects with different GJB2/GJB6 gene mutation profiles from a tertiary referral center in Northeastern Italy. We considered 57 patients with GJB2/GJB6 mutations presenting with congenital, non-syndromic SNHL, mainly coming from the Veneto region (Italy). The samples were screened for mutations in exons 1 and 2 of the GJB2 gene and for the GJB6 gene deletion del (GJB6-D13S1830). Free-field and air-conduction frequency-specific thresholds and the pure-tone average (PTA) were considered in the statistical analysis. Five patients (8.87%) had connexin gene mutations in simple heterozygosis, 15 (26.31%) in compound heterozygosis, 34 (59.64%) in homozygosis, and 3 (5.26%) with digenic patterns. The frequency-specific air-conduction thresholds showed significantly different mean values across the different genotypes (Roy's largest-root test, p = 0.0473). Despite the evidence already available on genetic SNHL, many new insights are to be expected. Further large-scale prospective studies including different populations are necessary to confirm these preliminary findings about the clinical and audiological features of patients with different GJB2/GJB6 gene mutation patterns.

Genetic diagnosis of childhood sensorineural hearing loss.

INTRODUCTION: Congenital/early-onset sensorineural hearing loss (SNHL) is one of the most common hereditary disorders in our environment. There is increasing awareness of the importance of an etiologic diagnosis, and genetic testing with next-generation sequencing (NGS) has the highest diagnostic yield. Our study shows the genetic results obtained in a cohort of patients with bilateral congenital/early-onset SNHL. MATERIALS AND METHODS: We included 105 children with bilateral SNHL that received genetic testing between 2019 and 2022. Genetic tests were performed with whole exome sequencing, analyzing genes related to hearing loss (virtual panel with 244 genes). RESULTS: 48% (50/105) of patients were genetically diagnosed. We identified pathogenic and likely pathogenic variants in 26 different genes, and the most frequently mutated genes were GJB2, USH2A and STRC. 52% (26/50) of variants identified produced non-syndromic hearing loss, 40% (20/50) produced syndromic hearing loss, and the resting 8% (4/50) could produce both non-syndromic and syndromic hearing loss. CONCLUSIONS: Genetic testing plays a vital role in the etiologic diagnosis of bilateral SNHL. Our cohort shows that genetic testing with NGS has a high diagnostic yield and can provide useful information for the clinical workup of patients.

Treatment following Triple-AAV Delivery in Mature Murine Model of Human CDH23-Associated Hearing Loss.

This study aimed to investigate the transduction efficiency of triple adeno-associated virus (AAV) vectors in the cochleae of adult mice, focusing on large-gene-associated hearing loss (HL). Additionally, we sought to evaluate the feasibility of cochlear gene therapy in a mouse model of human CDH23-mediated HL using the triple AAV approach. To create a reporter protein, we fused EGFP to mCherry, which was then divided into three parts, each packaged in a separate AAV2/2 vector. Four weeks after co-injecting the triple AAV vectors into 4-5-week-old mice, we assessed transduction efficiency. We found that up to 5.9% of inner hair cells were positive for both EGFP and mCherry. Subsequently, we developed triple Cdh23 AAV vectors for therapeutic purposes. After administering these vectors to 4- to 5-week-old C57/BL6 mice, we conducted auditory tests and immunohistochemistry studies over a period of 60 weeks. Co-injecting triple Cdh23-AAVs did not alter auditory function or lead to hair cell degeneration. In conclusion, this study confirms the feasibility of the triple-AAV approach for cochlear gene delivery. While this strategy did not produce any treatment effects, our findings suggest that large deafness genes could be potential future targets for cochlear gene therapy.

Recent advances in genetic etiology of non-syndromic deafness in children.

Congenital auditory impairment is a prevalent anomaly observed in approximately 2-3 per 1,000 infants. The consequences associated with hearing loss among children encompass the decline of verbal communication, linguistic skills, educational progress, social integration, cognitive aptitude, and overall well-being. Approaches to reversing or preventing genetic hearing loss are limited. Patients with mild and moderate hearing loss can only use hearing aids, while those with severe hearing loss can only acquire speech and language through cochlear implants. Both environmental and genetic factors contribute to the occurrence of congenital hearing loss, and advancements in our understanding of the pathophysiology and molecular mechanisms underlying hearing loss, coupled with recent progress in genetic testing techniques, will facilitate the development of innovative approaches for treatment and screening. In this paper, the latest research progress in genetic etiology of non-syndromic deafness in children with the highest incidence is summarized in order to provide help for personalized diagnosis and treatment of deafness in children.

Novel small molecule-mediated restoration of the surface expression and anion exchange activity of mutated pendrin causing Pendred syndrome and DFNB4.

Variants in SLC26A4 (pendrin) are the most common reasons for genetic hearing loss and vestibular dysfunction in East Asians. In patients with Pendred syndrome and DFNB4 (autosomal recessive type of genetic hearing loss 4), caused by variants in SLC26A4, the hearing function is residual at birth and deteriorates over several years, with no curative treatment for these disorders. In the present study, we revealed that a novel small molecule restores the expression and function of mutant pendrin. High-throughput screening of 54,000 small molecules was performed. We observed that pendrin corrector (PC2-1) increased the surface expression and anion exchange activity of p.H723R pendrin (H723R-PDS), the most prevalent genetic variant that causes Pendred syndrome and DFNB4. Furthermore, in endogenous H723R-PDS-expressing human nasal epithelial cells, PC2-1 significantly increased the surface expression of pendrin. PC2-1 exhibited high membrane permeability in vitro and high micromolar concentrations in the cochlear perilymph in vivo. In addition, neither inhibition of Kv11.1 activity in the human ether-a-go-go-related gene assay nor cell toxicity in the cell proliferation assay was observed at a high PC2-1 concentration (30 µM). These preclinical data support the hypothesis of the druggability of mutant pendrin using the novel corrector molecule PC2-1. In conclusion, PC2-1 may be a new therapeutic molecule for ameliorating hearing loss and treating vestibular disorders in patients with Pendred syndrome or DFNB4.

Recent advances in CRISPR-Cas system for the treatment of genetic hearing loss.

Genetic hearing loss has emerged as a significant public health concern that demands attention. Among the various treatment strategies, gene therapy based on gene editing technology is considered the most promising approach for addressing genetic hearing loss by repairing or eliminating mutated genes. The advent of the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas system has revolutionized gene therapy through its remarkable gene editing capabilities. This system has been extensively employed in mammalian gene editing and is currently being evaluated through clinical trials. Against this backdrop, this review aims to provide an overview of recent advances in utilizing the CRISPR-Cas system to treat genetic hearing loss. Additionally, we delve into the primary challenges and prospects associated with the current application of this system in addressing genetic hearing loss.

Novel Variant in CEP250 Causes Protein Mislocalization and Leads to Nonsyndromic Autosomal Recessive Type of Progressive Hearing Loss.

Genetic hearing loss is the most common hereditary sensorial disorder. Though more than 120 genes associated with deafness have been identified, unveiled causative genes and variants of diverse types of hearing loss remain. Herein, we identified a novel nonsense homozygous variant in CEP250 (c.3511C>T; p.Gln1171Ter) among the family members with progressive moderate sensorineural hearing loss in nonsyndromic autosomal recessive type but without retinal degeneration. CEP250 encodes C-Nap1 protein belonging to the CEP protein family, comprising 30 proteins that play roles in centrosome aggregation and cell cycle progression. The nonsense variant in CEP250 led to the early truncating protein of C-Nap1, which hindered centrosome localization; heterologous expression of CEP250 (c.3511C>T) in NIH3T3 cells within cilia expression condition revealed that the truncating C-Nap1 (p.Gln1171Ter) was not localized at the centrosome but was dispersed in the cytosol. In the murine adult cochlea, Cep250 was expressed in the inner and outer hair cells. Knockout mice of Cep250 showed significant hair cell degeneration and progressive hearing loss in auditory brainstem response. In conclusion, a nonsense variant in CEP250 results in a deficit of centrosome localization and hair cell degeneration in the cochlea, which is associated with the progression of hearing loss in humans and mice.

Causes of hearing loss and implantation age in a cohort of Danish pediatric cochlear implant recipients.

INTRODUCTION: Sensorineural hearing loss (SNHL) is the most common birth disorder. The cause of SNHL is heterogeneous and varies in different populations. Understanding the causes of a hearing loss (HL) predict the outcome of cochlear implantation and is of great importance in understanding the mechanism of the disease and in providing the best treatment. Undiagnosed and untreated HL has a profound effect on the acquisition of early communication skills, speech, language, academic, emotional, and psychosocial development in children. OBJECTIVES: To determine the cause of HL and implantation age in pediatric cochlear implant (CI) users in a Danish population. METHODS: Data of 100 children (54 females and 46 males), age 0-17 years, was analyzed. All of the children were implanted during 2020-2022. RESULTS: Hereditary HL was diagnosed in 44 cases (44%), with pathogenic variants in the SLC26A4 gene found in 14 cases (14%). Syndromic HL was diagnosed in 23 children (23%). Non-syndromic HL was diagnosed in 21 children (21%), where the most common genetic variation was found in the GJB2 gene. Acquired prenatal and postnatal sensory disorders TORCH risk factors were associated with HL in 25 cases (25%). Congenital CMV DNA was diagnosed in 23 samples (23%). The cause of the HL remained unknown for 31 (31%) children. In 70 (70%) of the participants the HL was diagnosed at time of newborn hearing screening (NHS). Twenty-three of the children were diagnosed with congenital severe to profound bilateral HL and were simultaneously implanted between 8 and 14 months (mean age 10.5 months). In the remaining 47 cases, the HL was progressive and the children were implanted when the HL reached the criteria for implantation. CONCLUSIONS: In the current study, the major causes of HL were alterations in the SLC26A4 gene: 13% with Pendred syndrome and 1% non-syndromic. Thirty-one (31%) had HL of unknown origin and almost half of these cases had inner ear malformations (n = 16).

Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review.

Autosomal dominant non-syndromic hearing loss (HL) typically occurs when only one dominant allele within the disease gene is sufficient to express the phenotype. Therefore, most patients diagnosed with autosomal dominant non-syndromic HL have a hearing-impaired parent, although de novo mutations should be considered in all cases of negative family history. To date, more than 50 genes and 80 loci have been identified for autosomal dominant non-syndromic HL. DFNA22 (MYO6 gene), DFNA8/12 (TECTA gene), DFNA20/26 (ACTG1 gene), DFNA6/14/38 (WFS1 gene), DFNA15 (POU4F3 gene), DFNA2A (KCNQ4 gene), and DFNA10 (EYA4 gene) are some of the most common forms of autosomal dominant non-syndromic HL. The characteristics of autosomal dominant non-syndromic HL are heterogenous. However, in most cases, HL tends to be bilateral, post-lingual in onset (childhood to early adulthood), high-frequency (sloping audiometric configuration), progressive, and variable in severity (mild to profound degree). DFNA1 (DIAPH1 gene) and DFNA6/14/38 (WFS1 gene) are the most common forms of autosomal dominant non-syndromic HL affecting low frequencies, while DFNA16 (unknown gene) is characterized by fluctuating HL. A long audiological follow-up is of paramount importance to identify hearing threshold deteriorations early and ensure prompt treatment with hearing aids or cochlear implants.

Rescue of auditory function by a single administration of AAV-TMPRSS3 gene therapy in aged mice of human recessive deafness DFNB8.

Patients with mutations in the TMPRSS3 gene suffer from recessive deafness DFNB8/DFNB10. For these patients, cochlear implantation is the only treatment option. Poor cochlear implantation outcomes are seen in some patients. To develop biological treatment for TMPRSS3 patients, we generated a knockin mouse model with a frequent human DFNB8 TMPRSS3 mutation. The Tmprss3A306T/A306T homozygous mice display delayed onset progressive hearing loss similar to human DFNB8 patients. Using AAV2 as a vector to carry a human TMPRSS3 gene, AAV2-hTMPRSS3 injection in the adult knockin mouse inner ear results in TMPRSS3 expression in the hair cells and the spiral ganglion neurons. A single AAV2-hTMPRSS3 injection in Tmprss3A306T/A306T mice of an average age of 18.5 months leads to sustained rescue of the auditory function to a level similar to wild-type mice. AAV2-hTMPRSS3 delivery rescues the hair cells and the spiral ganglions neurons. This study demonstrates successful gene therapy in an aged mouse model of human genetic deafness. It lays the foundation to develop AAV2-hTMPRSS3 gene therapy to treat DFNB8 patients, as a standalone therapy or in combination with cochlear implantation.

The applications of CRISPR/Cas-mediated genome editing in genetic hearing loss.

Hearing loss (HL) can be caused by a number of different genetic factors. Non-syndromic HL refers that HL occurs as an isolated symptom in an individual, whereas syndromic HL refers that HL is associated with other symptoms or abnormalities. To date, more than 140 genes have been identified as being associated with non-syndromic HL, and approximately 400 genetic syndromes can include HL as one of the clinical symptoms. However, no gene therapeutic approaches are currently available to restore or improve hearing. Therefore, there is an urgent necessity to elucidate the possible pathogenesis of specific mutations in HL-associated genes and to investigate the promising therapeutic strategies for genetic HL. The development of the CRISPR/Cas system has revolutionized the field of genome engineering, which has become an efficacious and cost-effective tool to foster genetic HL research. Moreover, several in vivo studies have demonstrated the therapeutic efficacy of the CRISPR/Cas-mediated treatments for specific genetic HL. In this review, we briefly introduce the progress in CRISPR/Cas technique as well as the understanding of genetic HL, and then we detail the recent achievements of CRISPR/Cas technique in disease modeling and therapeutic strategies for genetic HL. Furthermore, we discuss the challenges for the application of CRISPR/Cas technique in future clinical treatments.

Genetic Etiology of Nonsyndromic Hearing Loss in Hungarian Patients.

Hearing loss is the most prevalent sensory disorder worldwide. The majority of congenital nonsyndromic hearing loss (NSHL) cases are caused by hereditary factors. Previously, the majority of NSHL studies focused on the GJB2 gene; however, with the availability of next-generation sequencing (NGS) methods, the number of novel variants associated with NSHL has increased. The purpose of this study was to design effective genetic screening for a Hungarian population based on a pilot study with 139 NSHL patients. A stepwise, comprehensive genetic approach was developed, including bidirectional capillary sequencing, multiplex ligation-dependent probe amplification (MLPA), and an NGS panel of 108 hearing loss genes. With our results, a genetic diagnosis was possible for 92 patients. Sanger sequencing and MLPA identified the genetic background of 50% of these diagnosed cases, and the NGS panel identified another 16%. The vast majority (92%) of the diagnosed cases showed autosomal recessive inheritance and 76% were attributed to GJB2. The implementation of this stepwise analysis markedly increased our diagnostic yield and proved to be cost-effective as well.

[The genotype-phenotype correlation analysis and genetic counseling of hearing loss patients with novel KCNQ4 mutations].

Objective:To provide accurate genetic counseling, the genotype-phenotype correlation of the patients with KCNQ4mutations was analyzed. Methods:Two hearing loss families, 1807956（a five-generation family with 34 members） and 1707806（a three-generation family with 12 members） were recruited. The candidate variants were detected by next generation sequencing technology. Sanger sequencing was performed to verify the co-segregation of the phenotype in the recruited family members. According to American College of Medical Genetics and Genomics（ACMG） guideline, combined with clinical data, genetic testing, bioinformatic analysis and electrophysiological experiments, the pathogenicity of mutations was analyzed and genetic counseling was provided for family members. Results:The proband of family 1807956 was a pregnant woman, who carried KCNQ4 c.808T>G p.Y270D and developed hearing loss at the age of 15 years old, she had profound hearing loss in both ears, with middle-frequency highly affected. The proband of family 1707806 was an adolescent whose onset age was 11 years old, carrying KCNQ4 c.733G>A p.G245R, he presented with bilateral moderately severe hearing loss. The inheritance pattern of these two families were autosomal dominant inheritance. The two variants were missense mutations that were co-segregation in the two families and were not found in normal population. The mutations predicted by bioinformatic analysis tools were damaging and highly conserved in different species. Electrophysiological experiments showed that the function of the mutant ion channels was impaired. According to ACMG guideline, KCNQ4 c.808T>G was pathogenic, and KCNQ4 c.733G>A was likely pathogenic. Conclusion:The two mutations in this research were reported for the first time. The hearing loss of the patients showed heterogeneity, enriching the variation spectrum and clinical phenotype of KCNQ4.

The Absence of Permanent Sensorineural Hearing Loss in a Cohort of Children with SARS-CoV-2 Infection and the Importance of Performing the Audiological "Work-Up".

BACKGROUND: Currently, the novel coronavirus (SARS-CoV-2) causes an acute respiratory illness named COVID-19 and is a controversial risk factor for hearing loss (HL). Herein, we aim to describe the associated symptoms and to evaluate hearing function in the COVID-19 pediatric population. METHODS: A retrospective cross-sectional observational study was carried out on 37 children who contracted COVID-19 infection with no previous audio-vestibular disorders. Clinical data on the infections were collected, and an audiological assessment of all affected children was performed by using different diagnostic protocols according to their age. RESULTS: Fever, upper respiratory and gastrointestinal manifestations were common presentations of infection. Audiological function was normal in 30 (81.08%) children, while 7 children showed an increased hearing threshold: 6 (16.21%) had transient conductive hearing loss (CHL) due to middle ear effusion and normalized at the follow-up and 1 had sensorineural hearing loss (SNHL). A single child was affected by bilateral SNHL (2.7%); however, he underwent a complete audiological work-up leading to a diagnosis of genetic HL due to a MYO6 gene mutation which is causative of progressive or late onset SNHL. CONCLUSIONS: HL needs to be considered among the manifestations of COVID-19 in children, nevertheless, we found cases of transient CHL. The onset of HL during or following COVID-19 infection does not eliminate the indication for maintaining audiological surveillance and audiological work-ups, including genetic diagnosis, to avoid the risk of mistaking other causes of HL.

Usher Syndrome.

Usher syndrome (USH) is the most common genetic condition responsible for combined loss of hearing and vision. Balance disorders and bilateral vestibular areflexia are also observed in some cases. The syndrome was first described by Albrecht von Graefe in 1858, but later named by Charles Usher, who presented a large number of cases with hearing loss and retinopathy in 1914. USH has been grouped into three main clinical types: 1, 2, and 3, which are caused by mutations in different genes and are further divided into different subtypes. To date, nine causative genes have been identified and confirmed as responsible for the syndrome when mutated: MYO7A, USH1C, CDH23, PCDH15, and USH1G (SANS) for Usher type 1; USH2A, ADGRV1, and WHRN for Usher type 2; CLRN1 for Usher type 3. USH is inherited in an autosomal recessive pattern. Digenic, bi-allelic, and polygenic forms have also been reported, in addition to dominant or nonsyndromic forms of genetic mutations. This narrative review reports the causative forms, diagnosis, prognosis, epidemiology, rehabilitation, research, and new treatments of USH.

Genetic Causes of Hearing Loss in a Large Cohort of Cochlear Implant Recipients.

Understanding genetic causes of hearing loss can determine the pattern and course of a patient's hearing loss and may also predict outcomes after cochlear implantation. Our goal in this study was to evaluate genetic causes of hearing loss in a large cohort of adults and children with cochlear implants. We performed comprehensive genetic testing on all patients undergoing cochlear implantation. Of the 459 patients included in the study, 128 (28%) had positive genetic testing. In total, 44 genes were identified as causative. The top 5 genes implicated were GJB2 (20, 16%), TMPRSS3 (13, 10%), SLC26A4 (10, 8%), MYO7A (9, 7%), and MT-RNR1 (7, 5%). Pediatric patients had a higher diagnostic rate. This study lays the groundwork for future studies evaluating the relationship between genetic variation and cochlear implant performance.