Hearing loss is one of the most prevalent genetic disorders in humans. Locus and allelic heterogeneity cause fundamental challenges in hearing loss genetic diagnosis and management of patients and their families. This study examined the genetic profile of patients with prelingual hearing loss who were referred to the Genetic Foundation of Khorasan Razavi spanning over a decade. Deleterious variants in GJB2 were evaluated through Sanger sequencing among 745 non-syndromic hearing loss patients. Furthermore, exome sequencing was applied in 250 patients with negative GJB2 sequencing results and 30 patients with syndromic hearing loss. The findings revealed a relatively low frequency of GJB2 variants among the studied patients. Exome sequencing successfully identified the genetic causes of hearing loss in 70% of the patients. Moreover, variants in 10 genes, namely SLC26A4, MYO15A, TMPRSS3, TMC1, OTOF, CDH23, PJVK, MYO7A, TECTA, and PCDH15, accounted for 66% of the positive exome sequencing findings in this study. At least three prevalent founder alleles in the hearing-impaired population of eastern Iran were identified. This study emphasizes the efficiency of exome sequencing as a powerful tool for determining the etiology of prelingual hearing loss in the eastern Iranian population.

The primary etiology of congenital hearing loss is attributed to genetic factors, with GJB2 identified as a pivotal gene across diverse ethnic groups. Additionally, nonsyndromic hearing loss is predominantly inherited in an autosomal recessive manner. We used Sanger sequencing to analyze GJB2 in 17 deaf children from 13 unrelated Ivory Coast families. One family had two children born with severe congenital deafness and exhibited pathogenic compound heterozygous variants. These variants included a nonsense substitution (c.132G > A or p.Trp44Ter) and a newly discovered duplication of 7 base pairs (c.205_211dupTTCCCCA or p.Ser72ProfsTer32). Segregation testing confirmed these variants, marking the first identification of GJB2 in an Ivorian family with congenital hearing loss.

The co-occurrence of sensorineural hearing loss and male infertility has been reported in several instances, suggesting potential shared genetic underpinnings. One such example is the contiguous gene deletion of CATSPER2 and STRC genes, previously associated with deafness-infertility syndrome (DIS) in males. Fifteen males with both hearing loss and infertility from southern India after exclusion for the DIS contiguous gene deletion and the FOXI1 gene mutations are subjected to exome sequencing. This resolves the genetic etiology in four probands for both the phenotypes; In the remaining 11 probands, two each conclusively accounted for deafness and male infertility etiologies. Genetic heterogeneity is well reflected in both phenotypes. Four recessive (TRIOBP, SLC26A4, GJB2, COL4A3) and one dominant (SOX10) for the deafness; six recessive genes (LRGUK, DNAH9, ARMC4, DNAH2, RSPH6A, and ACE) for male infertility can be conclusively ascribed. LRGUK and RSPH6A genes are implicated earlier only in mice models, while the ARMC4 gene is implicated in chronic destructive airway diseases due to primary ciliary dyskinesia. This study would be the first to document the role of these genes in the male infertility phenotype in humans. The result suggests that deafness and infertility are independent events and do not segregate together among the probands.

UNASSIGNED: To explore the functional consequences of two common variants, p.V37I and c.299-300delAT in hearing loss associated gene GJB2.
UNASSIGNED: Connexin 26 expression and gap junctional permeability were studied in HEK 293T cells transfected with plasmids expressing GJB2 wild-type, p.V37I, or c.299-300delAT CX26 proteins with fluorescent tags. Functional analyses of different GJB2 haplotypes were performed to fully assess the alteration of ionic and small-molecule coupling.
UNASSIGNED: The p.V37I protein was localized at the plasma membrane, but failed to effectively transport intercellular propidium iodide or Ca2+ efficiently, indicating impairment of both biochemical and ionic coupling. The presence of GJB2 p.V37I appeared to increase the sensitivity of cells to H2O2 treatment. In contrast, the known variant c.299-300delAT protein was not transported to the cell membrane and could not form gap junctions, instead being confined to the cytoplasm. Ionic and biochemical coupling was defective in c.299-300delAT-transfected cells.
UNASSIGNED: The p.V37I and c.299-300delAT GJB2 mutations resulted in deficient gap junction-mediated coupling. Environmental factors may impact the functional consequences of GJB2 p.V37I. These results may inspire the development of molecular therapies targeting GJB2 mutations for hearing loss.

OBJECTIVE: Establishing the cause of hearing loss (HL) is important and rewarding, though not without its challenges. While our ability to identify the etiology for HL has improved with advances in scientific knowledge, a significant proportion of cases remain of unknown etiology. Recent protocol changes within the NHS Genomic Medicine Service support the utilization of the HL gene panel test, rather than individual gene tests. In light of these changes, determining the yield of these more extensive panel tests is important in informing future practice.
METHODS: Retrospective study.
METHODS: The Cochlear Implant (CI) Department at Great Ormond Street Hospital (GOSH).
METHODS: Four hundred seventy-six children with profound HL were identified from a database of referrals to the GOSH CI Department. Data on etiology of HL including genetic diagnosis was collected from hospital notes on an electronic patient records system and hospital genetics database.
RESULTS: We identified a positive result in 163/476 (34%) cases through the gene panel test, representing an additional 19% yield to current level 1 investigations. Genetic HL, including both syndromic (including those not covered by the HL gene panel) and nonsyndromic (209/476, 44%) was the most common etiology in our cohort. Perinatal, intrauterine, ototoxicity, meningitis, and encephalitis categories altogether comprised 97/476 (20%) cases.
CONCLUSIONS: Gene panel testing provides significant additional yield over current level 1 investigations which include GJB2 testing only. This has far-reaching implications for how we optimize investigations into HL in children and counsel families, and for future early interventions.

BACKGROUND: Recessive GJB2 variants, the most common genetic cause of hearing loss, may contribute to progressive sensorineural hearing loss (SNHL). The aim of this study is to build a realistic predictive model for GJB2-related SNHL using machine learning to enable personalized medical planning for timely intervention.
METHODS: Patients with SNHL with confirmed biallelic GJB2 variants in a nationwide cohort between 2005 and 2022 were included. Different data preprocessing protocols and computational algorithms were combined to construct a prediction model. We randomly divided the dataset into training, validation, and test sets at a ratio of 72:8:20, and repeated this process ten times to obtain an average result. The performance of the models was evaluated using the mean absolute error (MAE), which refers to the discrepancy between the predicted and actual hearing thresholds.
RESULTS: We enrolled 449 patients with 2184 audiograms available for deep learning analysis. SNHL progression was identified in all models and was independent of age, sex, and genotype. The average hearing progression rate was 0.61 dB HL per year. The best MAE for linear regression, multilayer perceptron, long short-term memory, and attention model were 4.42, 4.38, 4.34, and 4.76 dB HL, respectively. The long short-term memory model performed best with an average MAE of 4.34 dB HL and acceptable accuracy for up to 4 years.
CONCLUSIONS: We have developed a prognostic model that uses machine learning to approximate realistic hearing progression in GJB2-related SNHL, allowing for the design of individualized medical plans, such as recommending the optimal follow-up interval for this population.

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.
METHODS: 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.

OBJECTIVE: The crystal structure of the six protomers of gap junction protein beta 2 (GJB2) enables prediction of the effect(s) of an amino acid substitution, thereby facilitating investigation of molecular pathogenesis of missense variants of GJB2. This study mainly focused on R143W variant that causes hearing loss, and investigated the relationship between amino acid substitution and 3-D structural changes in GJB2.
METHODS: Patients with nonsyndromic hearing loss who appeared to have two GJB2 pathogenic variants, including the R143W variant, were investigated. Because the X-ray crystal structure of the six protomers of the GJB2 protein is known, R143W and structurally related variants of GJB2 were modeled using this crystal structure as a template. The wild-type crystal structure and the variant computer-aided model were observed and the differences in molecular interactions within the two were analyzed.
RESULTS: The predicted structure demonstrated that the hydrogen bond between R143 and N206 was important for the stability of the protomer structure. From this prediction, R143W related N206S and N206T variants showed loss of the hydrogen bond.
CONCLUSIONS: Investigation of the genotypes and clinical data in patients carrying the R143W variant on an allele indicated that severity of hearing loss depends largely on the levels of dysfunction of the pathogenic variant on the allele, whereas a patient with the homozygous R143W variant demonstrated profound hearing loss. We concluded that these hearing impairments may be due to destabilization of the protomer structure of GJB2 caused by the R143W variant.

In this study, we report a case of bilateral mild hearing loss and keratoderma caused by a gap junction beta-2 (GJB2) variant. The proband was a nine-year-old Japanese boy with bilateral mild hearing loss at birth. The proband\'s father, sister, paternal aunt, and cousins had mild sensorineural hearing loss. Further evaluation revealed keratoderma on the feet of the proband, father, sister, paternal aunt, and cousins. We identified a heterozygous c.250G>A (p.Val84Met) variant in GJB2 as the cause of the autosomal dominant syndromic hearing loss with the skin disorder in this Japanese family and delineated the pathological significance of the variant. The Val84Met variant in GJB2 contributes to the autosomal dominant form of syndromic hearing loss with keratoderma.

UNASSIGNED: Hearing loss is a common sensorineural dysfunction with a high incidence in China. Although genetic factors are important causes of hearing loss, hearing-related gene detection has not been widely adopted in China.
UNASSIGNED: Establishing a rapid and efficient method to simultaneously detect hotspot hearing loss gene mutations.
UNASSIGNED: A reverse dot blot assay combined with a flow-through hybridization technique was developed for the simultaneous detection of 13 hotspot mutations of 4 hearing loss-related genes including GJB2, GJB3, SLC26A4, and the mitochondrial gene MT-RNR1. This method involved PCR amplification systems and a hybridization platform.
UNASSIGNED: The technique can detect 13 hotspot mutations of 4 hearing loss-related genes. And a total of 213 blood samples were used to evaluate the availability of this method.
UNASSIGNED: Our reverse dot blot assay was a simple, rapid, accurate, and cost-effective method to identify hotspot mutations of 4 hearing loss-related genes in a Chinese population.