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Objective: By conducting genetic testing of hereditary hearing loss in pregnant women within 17 weeks of gestation in Dali areas, the importance of genetic testing and genetic counseling during pregnancy was emphasized. Methods: Twenty-one mutation sites of 4 hearing loss genes, including GJB2 , GJB3 , SLC26A4 and mtDNA , were detected by PCR amplification technology. The positive ratio, mutation ratio and ethnic distribution of positive samples were statistically described. Results: The positive ratios of GJB2 and SLC26A4 genes were 1.24% and 1.43%, respectively, with mutation rates of 40.62% and 46.88% in the positive samples, respectively. The positive ratio of GJB3 gene was 0.19%, and mtDNA mutation genes accounted for 0.14%, and all of them were mtDNA （Heterozygous）. There was only one case of GJB2 / SLC26A4 double positive multi-gene mutation, with a positive ratio of 0.05%. The frequency of GJB2 c. 235delC site was the highest, accounting for 65.38% of GJB2 mutation genes and 26.56% of mutation gene samples. Conclusion: GJB2 are the most common genes of hearing loss, and SLC26A4 c. 235delC site is the most common mutation site. Identifying the hearing loss mutation site is of great importance to prevent the birth of hereditary hearing loss children, and genetic diagnosis, genetic counseling, and appropriate intervention are crucial to alleviate congenital problems.GJB2 c. 235delC site is the most common mutation site. Identifying the hearing loss mutation site is of great importance to prevent the birth of hereditary hearing loss children, and genetic diagnosis, genetic counseling, and appropriate intervention are crucial to alleviate congenital problems., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Background: Cat eye syndrome (CES) is a rare congenital disease frequently caused by a partial tetrasomy of the proximal long (q) arm of chromosome 22, due to a small supernumerary marker chromosome (sSMC). CES patients show remarkable phenotypic variability. Despite the progress of molecular cytogenetic technology, the cause of phenotypic variability and the genotype-phenotype correlations remain unknown., Methods: We analyzed clinical and genetic data of a new patient with CES together with 27 previously reported ones with a confirmed genomic gain in the PubMed database between 2012 and 2023., Results: We reported a boy with CES carrying a 22q11.1-q11.21 duplication of 1.76 Mb tetrasomy (16888900_18644241, hg19) who presented currently rare or unreported clinical findings such as congenital aural atresia, hearing loss, PLSVC, and IVC. The results of the whole exome sequencing (WES) showed a heterozygous mutation of the GJB2 gene (NM_004004.6: exon2: c.109G > A). In addition, the results of our literature review showed that the presence of a classical sSMC was the most frequent cytogenetic abnormality in CES (82%). 63% of cases were in a homogenous state and 37% of cases were in a mosaic state. 72% of cases had a 1-2 Mb duplication. In the majority of CES patients the breakpoints in chromosome 22 are localized to a 50 kb region (18610000_18660000 bp). The CES critical region (CESCR) may be further delimited to a 0.3 Mb region (17799398_18111588 bp). Within this region CECR2, SLC25A18, ATP6V1E1, and BCL2L13 are strong candidate genes for causing the main CES phenotype. The ear anomalies are the most frequent features in CES patients (89%) and hearing loss was present in 36% of CES patients., Conclusions: The phenotypic features in CES are highly variable. Our findings expand the symptom spectrum of CES and lay the foundation for better delineating the clinical phenotype, molecular cytogenetic features associated with CES and genotype-phenotype correlations. We recommend performing WES to rule out the involvement of other genetic factors in the patient's phenotype. In addition, our findings also highlight the need for genetic counseling and recurrence risk assessment., (© 2024. The Author(s).)

Hearing loss affects around 5% of the global population. Two preliminary studies have described genetic variants in sporadic individuals with hearing loss from Pakistan. Here we extend these studies to determine the spectrum of variants in a cohort of individuals with no previous history of hearing loss. Individuals with hearing loss born to consanguineous couples were identified from special schools. Audiograms were assessed. DNA from participants negative for GJB2 pathogenic variants was subjected to exome sequencing. Data were filtered to include variants with frequencies < 0.01 in the public databases. The effects of the missense variants on respective amino acids were analyzed by using PyMol software. Among the 44 participants, hearing loss was moderate for two individuals; 14 exhibited moderately-severe hearing loss while 25 had a severe degree of hearing loss. Hearing loss was reported to have been progressive in four participants and was currently profound in three participants. Variants were unambiguously identified in 17 genes, of which the majority affected SLC26A4. CDH23, MYO15A and OTOF were other significant contributors. Deleterious variants detected in two genes suggest new associations for hearing loss. Molecular characterization of hearing loss in our cohort revealed high genetic heterogeneity with a 75% diagnostic rate., (© 2024. The Author(s).)

Background: Hereditary hearing loss is a rare hereditary condition that has a significant presence in consanguineous populations. Despite its prevalence, hearing loss is marked by substantial genetic diversity, which poses challenges for diagnosis and screening, particularly in cases with no clear family history or when the impact of the genetic variant requires functional analysis, such as in the case of missense mutations and UTR variants. The advent of next-generation sequencing (NGS) has transformed the identification of genes and variants linked to various conditions, including hearing loss. However, there remains a high proportion of undiagnosed patients, attributable to various factors, including limitations in sequencing coverage and gaps in our knowledge of the entire genome, among other factors. In this study, our objective was to comprehensively identify the spectrum of genes and variants associated with hearing loss in a cohort of 106 affected individuals from the UAE., Results: In this study, we investigated 106 sporadic cases of hearing impairment and performed genetic analyses to identify causative mutations. Screening of the GJB2 gene in these cases revealed its involvement in 24 affected individuals, with specific mutations identified. For individuals without GJB2 mutations, whole exome sequencing (WES) was conducted. WES revealed 33 genetic variants, including 6 homozygous and 27 heterozygous DNA changes, two of which were previously implicated in hearing loss, while 25 variants were novel. We also observed multiple potential pathogenic heterozygous variants across different genes in some cases. Notably, a significant proportion of cases remained without potential pathogenic variants., Conclusions: Our findings confirm the complex genetic landscape of hearing loss and the limitations of WES in achieving a 100% diagnostic rate, especially in conditions characterized by genetic heterogeneity. These results contribute to our understanding of the genetic basis of hearing loss and emphasize the need for further research and comprehensive genetic analyses to elucidate the underlying causes of this condition., (© 2024. The Author(s).)

Background: Hearing loss (HL) is a common sensory impairment worldwide, with genetic and environmental factors contributing to its occurrence. Next Generation Sequencing (NGS) plays a crucial role in identifying the genetic factors involved in this heterogeneous disorder., Methods and Results: In this study, a total of 9 unrelated Iranian families, each having at least one affected individual who tested negative for mutations in GJB2, underwent screening using whole exome sequencing (WES). The pathogenicity and novelty of the identified variant was checked using various databases. Co-segregation study was also performed to confirm the presence of the candidate variants in parents. Plus, The pathogenicity of the detected variant was assessed through in silico analysis using a number of mutation prediction software tools. Among the 9 investigated families, hearing loss-causing genes were identified in 6 families. the mutations were observed in USH2A, CLRN1, BSND, SLC26A4, and MITF, with two of the identified mutations being novel., Conclusion: Discovering additional variants and broadening the range of mutations associated with hearing impairment has the potential to enhance the diagnostic effectiveness of molecular testing in patient screening, and can also lead to improved counseling aimed at reducing the risk of affected offspring for high-risk couples., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Objectives: 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., Conclusion: 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., (© 2024. The Author(s).)

Objective: To analyze the mutation spectrum of 23-site chip newborn deafness genetic screening in Beijing, and to provide basis for genetic counseling and clinical diagnosis and treatment. Methods: The study included 21 006 babies born in Beijing from December 2022 to June 2023. All subjects underwent newborn deafness genetic screening in Beijing Tongren Hospital, covering 23 variants in 4 genes, the GJB2 gene（c.35delG, c.176&#95;191del16, c.235delC, c.299&#95;300delAT, c.109G>A, c.257C>G, c.512insAACG, c.427C>T, c.35insG）, SLC26A4 gene（c.919-2A>G, c.2168A>G, c.1174A>T, c.1226G>A, c.1229C>T, c.1975G>C, c.2027T>A, c.589G>A, c.1707+5G>A, c.917insG, c.281C>T）, Mt12SrRNA （m.1555A>G, m.1494C>T） and GJB3 gene（c.538C>T）. The mutation detection rate and allele frequency were analyzed. Results: The overall mutation detection rate was 11.516%（2 419/21 006）, with the GJB2 gene being the most frequently involved at 9.097%（1 911/21 006）, followed by the SLC26A4 gene at 2.123%（446/21 006）, the GJB3 gene at 0.362%（76/21 006） and Mt12SrRNA at 0.176%（37/21 006）. Among the GJB2 genes, c.109G>A and c.235delC mutation detection rates were the highest, with 6.579%（1 382/21 006） and 1.795%（377/21 006）, respectively. Of the SLC26A4 genes, c.919-2A>G and c.2168A>G had the highest mutation rates of 1.423%（299/21 006） and 0.233%（49/21 106）, respectively. Regarding the allele frequency, GJB2 c.109G>A was the most common variant with an allele frequency of 3.359%（1 411/42 012）, followed by the GJB2 c.235delC at 0.897%（377/42 012） and the SLC26A4 c.919-2A>G at 0.719%（302/42 012）. Conclusion: 23-site chip newborn deafness genetic screening in Beijing showed that GJB2 c.109G>A mutation detection rate and allele frequency were the highest. This study has enriched the epidemiological data of 23-site chip genetic screening mutation profiles for neonatal deafness, which can provide evidence for clinical practice., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Hearing loss is the most predominant sensory defect occurring in pediatrics, of which, 66% cases are attributed to genetic factors. The prevalence of hereditary hearing loss increases in consanguineous populations, and the prevalence of hearing loss in Qatar is 5.2%. We aimed to investigate the genetic basis of nonsyndromic hearing loss (NSHL) in Qatar and to evaluate the diagnostic yield of different genetic tests available. A retrospective chart review was conducted for 59 pediatric patients with NSHL referred to the Department of Adult and Pediatric Medical Genetics at Hamad Medical Corporation in Qatar, and who underwent at least one genetic test. Out of the 59 patients, 39 were solved cases due to 19 variants in 11 genes and two copy number variants that explained the NSHL phenotype. Of them 2 cases were initially uncertain and were reclassified using familial segregation. Around 36.8% of the single variants were in GJB2 gene and c.35delG was the most common recurrent variant seen in solved cases. We detected the c.283C > T variant in FGF3 that was seen in a Qatari patient and found to be associated with NSHL for the first time. The overall diagnostic yield was 30.7%, and the diagnostic yield was significantly associated with genetic testing using GJB2 sequencing and using the hearing loss (HL) gene panel. The diagnostic yield for targeted familial testing was 60% (n = 3 patients) and for gene panel was 50% (n = 5). Thus, we recommend using GJB2 gene sequencing as a first-tier genetic test and HL gene panel as a second-tier genetic test for NSHL. Our work provided new insights into the genetic pool of NSHL among Arabs and highlights its unique diversity, this is believed to help further in the diagnostic and management options for NSHL Arab patients., (© 2024. The Author(s).)

Congenital hearing loss is the most common birth defect, estimated to affect 2-3 in every 1000 births, with ~50-60% of those related to genetic causes. Technological advances enabled the identification of hundreds of genes related to hearing loss (HL), with important implications for patients, their families, and the community. Despite these advances, in Latin America, the population with hearing loss remains underdiagnosed, with most studies focusing on a single locus encompassing the GJB2 / GJB6 genes. Here we discuss how current and emerging genetic knowledge has the potential to alter the approach to diagnosis and management of hearing loss, which is the current situation in Latin America, and the barriers that still need to be overcome.

Background and Aims: Hearing loss is a common sensorineural disease with genetic heterogeneity. More than 140 genes are known to cause hereditary hearing loss. We aim to uncover the etiologies of hearing loss and provide patients with reasonable reproductive choices., Materials and Methods: Total 825 participants were recruited, including 74 individuals, 47 couples, and 219 families, to identify the molecular etiologies of hearing loss using next-generation sequencing (NGS). Novel mutations were verified with a minigene splicing assay and the construction of three-dimensional protein models., Results: A positive molecular diagnosis was obtained for 244 patients, a rate of 63.05 %. Total 470 mutations were identified in 18 causative genes in positive patients. The most common genes mutated were GJB2 and SLC26A4. 47 novel mutations were identified. Further analysis predicted that two splicing mutations would cause abnormal mRNA splicing and three missense mutations would affect the protein structure. The results of prenatal diagnosis showed that the genotypes of 15 fetuses were the same as the probands., Conclusion: Our findings expand the mutation spectrum of hearing loss and highlight the importance of genetic diagnosis and prenatal diagnosis to allow accurate and personalized guidance for those at high risk of deafness., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: To analyze the genotype distribution and frequency of hearing loss genes in newborn population and evaluate the clinical value of genetic screening policy in China., Methods: Genetic screening for hearing loss was offered to 84,029 neonates between March 2019 and December 2021, of whom 77,647 newborns accepted the screening program with one-year follow-up. The genotyping of 15 hot spot variants in GJB2, GJB3, SLC26A4, and MT-RNR1 was performed on microarray platform., Results: A total of 3.05% (2369/77,647) newborns carried at least one genetic hearing loss-associated variant, indicated for early preventive management. The carrier frequency of GJB2 gene was the highest, at 1.48% (1147/77,647), followed by SLC26A4 gene at 1.07% (831/77,647), and GJB3 gene at 0.23% (181/77,647). GJB2 c.235delC variant and SLC26A4 IVS7-2A>G variant were the most common allelic variants with allele frequency of 0.6304% (979/155,294) and 0.3992% (620/155,294), respectively. 10 children are identified as homozygous or compound heterozygous for pathogenic variants (4 in GJB2, 6 in SLC26A4), and 7 of these infants had passed the hearing screening. Following up of the genetically screened newborns revealed that genetic screening detected more hearing-impaired infants than hearing screening alone. Genetic screening helped identify the infants who had passed the initial hearing screening, and reduced time for diagnosis and intervention of hearing aid. In addition, we identified 234 newborns (0.30%, 234/77,647) susceptible to preventable aminoglycoside antibiotic ototoxicity undetectable by hearing screening., Conclusion: We performed the largest-scale neonatal carrier screening for hearing loss genes in Southeast China. Our results indicated that genetic screening is an important complementation to conventional hearing screening. Our practice and experience may facilitate the application and development of neonatal genetic screening policy in mainland China., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Objectives: The molecular etiology of non-syndromic hearing loss (NSHL) in Southeastern China (Fujian) has not been precisely identified. our study selected patients with NSHL and analyzed their causative genes, which helped to improve the accuracy of the diagnosis of hereditary hearing loss (HHL) and its treatment., Methods: 251 unrelated patients who attended the otolaryngology clinic of Fujian Maternal and Child Health Hospital with hearing loss were enrolled to our study. All patients had genetic tests and listening tests, of which 251 were diagnosed with NSHL. In addition, we used whole-exome sequencing (WES) in a patient who has a significant family history of HHL but negative for gene chip testing, as well as in his family members., Result: Among of 251 patients, Nucleotide changes were found in 63 cases (25.09%), including 34 located in GJB2(13.5%, including 235delC and 299&#95;300delAT), 13 located in SLC26A4(5.18%, including c.919-2G > A and 2168 A > G), 1 located in GJB3(0.4%,538C > T) and 16 located in mtDNA12SrRNA (6.37%,1555 A > G). In addition, we discuss the process of identifying novel PLS1 mutations from 251 patients., Conclusion: Our results demonstrate the conventional deafness gene mutation in 251 NSHL patients in Fujian, China. Compared with the other area of China, we have a lower detection rate, but GJB2 235delC remains the most common mutation in Fujian. In addition, we discuss the process of discovering novel mutation locus for deafness, which provides an understanding for deafness diagnosis and genetic testing., Competing Interests: Declaration of competing interest All authors declare that they have no any conflict of interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

We aimed to investigate whether the degree of hearing loss with GJB2 mutations could be predicted by distinguishing between truncating and non-truncating mutations and whether the genotype could predict the hearing loss level. Additionally, we examined the progression of hearing loss in individuals monitored for over 2 years for an average of 6.9 years. The proportion of truncating mutations was higher in patients with profound and severe hearing loss, but it was not accurate enough to predict the degree of hearing loss. Via genotype analysis, mutations of the p.Arg143Trp variants were associated with profound hearing loss, while mutations of the p.Leu79Cysfs*3 allele exhibited a wide range of hearing loss, suggesting that specific genotypes can predict the hearing loss level. Notably, there were only three cases of progression in four ears, all of which involved the p.Leu79Cysfs*3 mutation. Over the long-term follow-up, 4000 Hz was significant, and there was a trend of progression at 250 Hz, suggesting that close monitoring at these frequencies during follow-up may be crucial to confirm progression. The progression of hearing loss was observed in moderate or severe hearing loss cases at the time of the initial diagnosis, emphasizing that children with this level of hearing loss need regular follow-ups.

Background: HL is the second most common congenital disability in China, and its high incidence brings a serious burden of medical and educational sequelae. HL genetic screening enables the identification of individuals with inherited HL and carriers in a large scale., Objective: This study aimed to measure the detection rates of hearing loss (HL)-associated gene mutations in the Gannan population. The molecular etiology and risk factors of hereditary HL were also analyzed., Methods: In total, 119,606 newborns from 18 districts of Gannan were enrolled in this multi-center study conducted between April 2019 and April 2021. Otoacoustic Emission (OAE) was used for primary hearing screening 3 days after birth in quiet conditions, and OAE combined with automated auditory brainstem response (AABR) was applied 29-42 days after birth for those who failed or missed the initial screening. Meanwhile, high-throughput sequencing of hotspot HL-associated mutations in GJB2, GJB3, MTRNR1, and SLC26A4 were performed., Results: Among the 119,606 newborns, 7796 (6.52%) failed the hearing screening. Genetic screening revealed that 5092 neonates (4.26%) carried HL-associated mutations. The detection rate of GJB2, SLC26A4, MTRNR1 and GJB3 mutations were 2.09%, 1.51%, 0.42% and 0.24%, respectively. The most prevalent variant was GJB2 c.235delC (1.74%). The second most prevalent variant was SLC26A4 c.919-2A > G (0.93%). The population who failed the hearing screening had a lower proportion (24.64%) of SLC26A4 gene variants compared to the population who passed (37.46%). Genetic screening identified 4612 (3.86%) carriers who were normal in hearing screenings. The concurrent hearing and genetic screening identified 480 (0.40%) neonates at high risk for hereditary HL., Conclusions: The results of this study suggest that the concurrent hearing screening and high-throughput genetic screening would greatly improve the effectiveness of newborn HL programs. This integration also facilitates the management of congenital HL, and aids in the prevention of aminoglycoside antibiotics-induced HL., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Gap junction protein beta 2 ( GJB2 ) p.V37I mutations are the most important hereditary cause of sensorineural hearing loss (SNHL) in Taiwan. Hearing outcomes are associated with hearing levels at baseline and the duration of follow-up. However, the audiological features of GJB2 p.V37I mutations in the adult population are unknown. The objectives of the present study were to investigate the audiological features, progression rate, and allele frequency of GJB2 p.V37I mutations among an adult Taiwanese population., Methods: Subjects of this case-control study were chosen from 13,580 participants of the Taiwan Precision Medicine Initiative. The genetic variations of GJB2 p.V37I were determined by polymerase chain reaction. We analyzed existing pure-tone threshold data from 38 individuals who were homozygous or compound heterozygotes for GJB2 p.V37I, 129 who were heterozygotes, and 602 individuals who were wild-type. Phenome-wide association studies (PheWAS) analysis was also performed to identify phenotypes associated with GJB2 p.V37I., Results: The minor allele frequency of GJB2 p.V37I was 0.92% in our study population. The mean hearing level of participants with a p.V37I mutation indicated moderate to severe hearing loss with 38.2% ± 22.3% binaural hearing impairment. GJB2 p.V37I was associated with an increased risk of hearing disability (odds ratio: 21.46, 95% confidence interval: 8.62 to 53.44, p < 0.001) in an autosomal recessive pattern. In addition, PheWAS discovered a significant association between GJB2 p.V37I and fracture of the humerus. GJB2 p.V37I is a pathogenic and prevalent variant of SNHL among the adult population., Conclusions: The present study recommends patients with known GJB2 p.V37I mutations receive regular audiometric evaluation and genetic counseling. Early assistive listening device intervention is suggested to improve the quality of hearing., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

One of the most common forms of genetic deafness has been predominantly associated with pathogenic variants in the GJB2 gene, encoding transmembrane protein connexin 26 (Cx26). The Cx26 molecule consists of an N-terminal domain (NT), four transmembrane domains (TM1-TM4), two extracellular loops (EL1 and EL2), a cytoplasmic loop, and a C-terminus (CT). Pathogenic variants in the GJB2 gene, resulting in amino acid substitutions scattered across the Cx26 domains, lead to a variety of clinical outcomes, including the most common non-syndromic autosomal recessive deafness (DFNB1A), autosomal dominant deafness (DFNA3A), as well as syndromic forms combining hearing loss and skin disorders. However, for rare and poorly documented variants, information on the mode of inheritance is often lacking. Numerous in vitro studies have been conducted to elucidate the functional consequences of pathogenic GJB2 variants leading to amino acid substitutions in different domains of Cx26 protein. In this work, we summarized all available data on a mode of inheritance of pathogenic GJB2 variants leading to amino acid substitutions and reviewed published information on their functional effects, with an emphasis on their localization in certain Cx26 domains.

Background: Hainan Province is the southernmost island in China, far from the mainland, and the resident population changes little. In order to understand the mutation spectrum in Hainan and provide effective genetic counseling for deaf people, we carried out genetic analysis on the non-comprehensive hearing impairment in this population. Therefore, in this study, 183 children with moderate sensorineural deafness in the northeast of Hainan were analyzed with susceptibility gene carrying and gene mutation, providing some reference for hainan to guide the prevention and treatment of deafness., Methods: Complete clinical evaluations were performed on 183 unrelated patients with a non-syndromic hearing impairment from Hainan Province. Each subject was screened for common mutations using the matrix-assisted laser desorption ionization-time of flight mass spectrometry, including GJB2 c.35delG,c.235delC,c.299&#95;300del AT,c.176&#95;191del16,c.167delT; GJB3 c.538 C>T,c.547G >A;SLC26A4 IVS7-2 A>G,c.2168 A>G,c.1174A>T,c.1229 C>T,c.1226G>A,c.1975G>C,c.2027T>A,c.2162C>T,c.281C>T,c.589G>A,IVS15+5G>A; and mtRNA 1494 C>T,1555 A>G., Results: Genetic analysis showed that GJB2, SLC26A4, and mitochondrial M. 1555A > G mutations accounted for 7.10%, 8.74%, and 0.55% of the etiology of non-syndromic hearing impairment, respectively. Common mutations include GJB2 C. 235delC, SLC26A4 c.I vs7-2a →G, C. 2168A→G, and mitochondrial M. 1555A > G. The total mutation rate in Hainan was 16.39%., Conclusion: Our study is the first one to carry out genetic analysis on non-syndromic hearing impairment in Hainan. The results show that in the cases of non-syndromic hearing impairment in these areas, there is a clear genetic cause accounted for 16.39%, and the mutation hot spots are mainly GJB2 and SLC26A4, and SLC26A4 is the most common mutation site. This study provides useful and targeted information for genetic counseling of deafness in people with non-syndromic hearing impairment in Hainan.

The connexin gene family is the most prevalent gene that contributes to hearing loss. Connexins 26 and 30, encoded by GJB2 and GJB6 , respectively, are the most abundantly expressed connexins in the inner ear. Connexin 43, which is encoded by GJA1 , appears to be widely expressed in various organs, including the heart, skin, the brain, and the inner ear. The mutations that arise in GJB2 , GJB6 , and GJA1 can all result in comprehensive or non-comprehensive genetic deafness in newborns. As it is predicted that connexins include at least 20 isoforms in humans, the biosynthesis, structural composition, and degradation of connexins must be precisely regulated so that the gap junctions can properly operate. Certain mutations result in connexins possessing a faulty subcellular localization, failing to transport to the cell membrane and preventing gap junction formation, ultimately leading to connexin dysfunction and hearing loss. In this review, we provide a discussion of the transport models for connexin 43, connexins 30 and 26, mutations affecting trafficking pathways of these connexins, the existing controversies in the trafficking pathways of connexins, and the molecules involved in connexin trafficking and their functions. This review can contribute to a new way of understanding the etiological principles of connexin mutations and finding therapeutic strategies for hereditary deafness.

Concurrent screening has been proven to provide a comprehensive approach for management of congenital deafness and prevention of ototoxicity. The SLC26A4 gene is associated with late-onset hearing loss and is of great clinical concern. For much earlier detection of newborns with deafness-causing mutations in the SLC26A4 gene, the Beijing Municipal Government launched a chip for optimized genetic screening of 15 variants of 4 genes causing deafness based on a chip to screen for 9 variants of 4 genes, and 6 variants of the SLC26A4 gene have now been added. To ascertain the advantage of a screening chip including 15 variants of 4 genes, the trends in concurrent hearing and genetic screening were analyzed in 2019 and 2020. Subjects were 76,460 newborns who underwent concurrent hearing and genetic screening at 24 maternal and child care centers in Beijing from January 2019 to December 2020. Hearing screening was conducted using transiently evoked otoacoustic emissions (TEOAEs), distortion product otoacoustic emissions (DPOAE), or the automated auditory brainstem response (AABR). Dried blood spots were collected for genetic testing and 15 variants of 4 genes, namely GJB2, SLC26A4, mtDNA 12S rRNA, and GJB3, were screened for using a DNA microarray platform. The initial referral rate for hearing screening decreased from 3.60% (1,502/41,690) in 2019 to 3.23% (1,124/34,770) in 2020, and the total referral rate for hearing screening dropped form 0.57% (236/41,690) in 2019 to 0.54% (187/34,770) in 2020, indicating the reduced false positive rate of newborn hearing screening and policies to prevent hearing loss conducted by the Beijing Municipal Government have had a significant effect. Positivity according to genetic screening was similar in 2019 (4.970%, 2,072/41,690) and 2020 (4.863%,1,691/34,770), and the most frequent mutant alleles were c.235 del C in the GJB2 gene, followed by c.919-2 A > G in the SLC26A4 gene, and c.299 del AT in the GJB2 gene. In this cohort study, 71.43% (5/7) of newborns with 2 variants of the SLC26A4 gene were screened for newly added mutations, and 28.57% (2/7) of newborns with 2 variants of the SLC26A4 gene passed hearing screening, suggesting that a screening chip including 15 variants of 4 genes was superior at early detection of hearing loss, and especially in early identification of newborns with deafness-causing mutations in the SLC26A4 gene. These findings have clinical significance.

Objectives: Hearing loss is one of the most common heterogeneous complicated disorders worldwide. We previously analyzed the results of published data on non-syndromic hearing loss in the Iranian population systematically. A broad range of genes is a challenge for molecular screening and clinical diagnosis in our populations on the ground of distinct genetics. The aim of this study was to analyze the role and frequency of the variants accountable for non-syndromic hearing loss (NSHL) in the Iranian population. These were identified with different methods including whole exome sequencing (WES), next-generation sequencing (NGS), targeted genomic enrichment and massively parallel sequencing (TGE + MPS), autozygosity mapping, STR markers, linkage analysis, and direct sequencing. This is the comprehensively study focusing on classifying 13 common NSHL genes according to their frequencies. Previous studies have not studied different regions and the Iranian population, and this is the definitive study on the topic., Methods: We searched Scopus, PubMed, Science Direct databases, and Google Scholar. After a systematic review of the evidence 95 studies were considered then 31 studies were eligible for meta-analysis. In total, 6995 families, 358 variants, and 117 novel variants were included. Statistical analyses were conducted using Stata SE version 11 software. The inverse variance method enjoyed combining data. Heterogeneity of the preliminary results was assessed using Q (Cochrane test), and I square index. Random effects or fixed models were applied to combine the results, relying on the degree of heterogeneity. Point and pooled prevalence of variants acting on different regions were illustrated by forest plots., Results: The total prevalence of at least one variant of GJB2 and SLC26A genes was estimated at 26% and 5%, respectively. Variant c.35delG accounted for 18% of the GJB2 variants while 1% of these variants were novel ones. The next most common variants in the GJB2 gene were c.109G>A at 3.5% and c.-23+1G>A at 2.3%. Moreover, the prevalence of GJB2 gene variants varied on average 0.002% from one region to another in Iran (p=0.849). Our meta-analysis also showed that the frequency of at least one variant of MYO15A varied between 1.2% and 12.5%. Corresponding prevalences for the other variants were as follows: ILDR1 (3.5%-3.7%), CDH23 (2%-10%), PJVK (1.4%-33%), TECTA (1.3%-6.7%), MYO6 (2%-4.8%), TMC1 (1.8%-2%), MYO7A (0.7%-5%), MARVELD2 (0.7-5%), OTOF (0.7%-4%), LRTOMT (0.7%-2.5%). Finally, we did not find any relationship between geographic area and the presence of these variants., Conclusion: GJB2 gene variants were the most common cause of NSHL in Iran. Understanding the prevalence of NSHL gene frequency in Iran may be the foundation for future studies in an Iranian population which may lead to future NSHL therapy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

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 genetic etiology of non-syndromic hearing impairment (NSHI) is highly heterogeneous with over 124 distinct genes identified. The wide spectrum of implicated genes has challenged the implementation of molecular diagnosis with equal clinical validity in all settings. Differential frequencies of allelic variants in the most common NSHI causal gene, gap junction beta 2 ( GJB2 ), has been described as stemming from the segregation of a founder variant and/or spontaneous germline variant hot spots. We aimed to systematically review the global distribution and provenance of founder variants associated with NSHI. The study protocol was registered on PROSPERO, the International Prospective Register of Systematic Reviews, with the registration number "CRD42020198573". Data from 52 reports, involving 27,959 study participants from 24 countries, reporting 56 founder pathogenic or likely pathogenic (P/LP) variants in 14 genes ( GJB2 , GJB6 , GSDME , TMC1 , TMIE , TMPRSS3 , KCNQ4 , PJVK , OTOF , EYA4 , MYO15A , PDZD7 , CLDN14 , and CDH23 ), were reviewed. Varied number short tandem repeats (STRs) and single nucleotide polymorphisms (SNPs) were used for haplotype analysis to identify the shared ancestral informative markers in a linkage disequilibrium and variants' origins, age estimates, and common ancestry computations in the reviewed reports. Asia recorded the highest number of NSHI founder variants (85.7%; 48/56), with variants in all 14 genes, followed by Europe (16.1%; 9/56). GJB2 had the highest number of ethnic-specific P/LP founder variants. This review reports on the global distribution of NSHI founder variants and relates their evolution to population migration history, bottleneck events, and demographic changes in populations linked with the early evolution of deleterious founder alleles. International migration and regional and cultural intermarriage, coupled to rapid population growth, may have contributed to re-shaping the genetic architecture and structural dynamics of populations segregating these pathogenic founder variants. We have highlighted and showed the paucity of data on hearing impairment (HI) variants in Africa, establishing unexplored opportunities in genetic traits.

More than 50% of congenital hearing loss is hereditary, in which the majority form is non-syndromic. In this study we estimate the most prevalent pathogenic genetic changes in an Ossetian cohort of patients. This is useful for local public health officials to promote genetic counseling of affected families with regard to high allele frequencies of prevalent pathogenic variants and assortative mating in the community of people with hearing loss. In this study, genetic heterogeneity of hereditary non-syndromic sensorineural hearing loss (NSNHL) in a cohort of 109 patients and an assessment of the frequency of two GJB2 gene pathogenic variants in a cohort of 349 healthy individuals from the populations of the Republic of North Ossetia-Alania (RNO-Alania) were assessed. The molecular genetic cause of NSNHL in the GJB2 gene in RNO-Alania was confirmed in ~30% of the cases, including ~27% in Ossetians. In Russian patients, the most frequent variant is GJB2 :c.35delG (~83%). The GJB2 :c.358&#95;360delGAG variant was found to be the most frequent among Ossetians (~54%). Two genetic variants in GJB2 , c.35delG and c.358&#95;360delGAG, accounted for 91% of GJB2 pathogenic alleles in the Ossetian patients. A search for large genome rearrangements revealed etiological cause in two Ossetian patients, a deletion at the POU3F4 gene locus associated with X-linked hearing loss (type DFNX2). In another Ossetian patient, a biallelic pathogenic variant in the MYO15A gene caused hearing loss type DFNB3 was identified, and in one Russian family a heterozygous MYH14 gene variant associated with dominant NSNHL was found. Thus, the informative value of the diagnosis was ~37% among all patients with NSNHL from RNO-Alania and ~32% among the Ossetians. These estimates correspond to the literature data on the fraction of recessive genetic forms of hearing loss within the affected population. The importance of this study consists not only in the estimation of the most prevalent pathogenic genetic changes in the Ossetian cohort of patients which could be useful for the public health but also in the genetic counselling of the affected families with regard to the high allele frequencies of revealed pathogenic variants as well as to the assortative mating in community of people with hearing loss., Competing Interests: The authors declare that they have no competing interests., (© 2023 Petrova et al.)

BACKGROUND The GJB2 gene is reported to be the main hereditary factor responsible for non-syndromic hearing impairment in infants. Several kinds of hearing loss have been linked to elevated inflammatory markers. This study aimed to evaluate serum levels of IL-2, IL-4, IL-6, IL-10, IL-17, alpha-TNF, and γ-IFN and the severity of hearing loss. MATERIAL AND METHODS Ninety newborns were divided into 3 groups: severe hearing impairment (31 infants), moderate hearing impairment (30 infants), and normal hearing (29 infants). Hearing screening was performed using otoacoustic emissions test. Mutations of the GJB2 gene were detected with Sanger sequencing. The patients had DNFB1 mutation. Seven blood inflammatory markers were tested using Cytometric Bead Array. We performed the t test to examine differences in expression of 7 inflammatory markers between sexes in the groups. The correlation between indicators within groups was studied using the Pearson correlation test. Correlation of different indicators among groups was studied using the Spearman correlation test. RESULTS When compared among the 3 groups (severe, moderate hearing impairment, and normal hearing group), we found that IL-10 had a positive correlation with the severity of GJB2-associated hearing loss, which was statistically significant (P<0.05). CONCLUSIONS This research aimed to assess the relationship of 7 serum inflammatory markers with GJB2-associated hearing loss in infants. Inflammatory marker IL-10 had a positive correlation with the severity of GJB2-associated infant hearing loss, and it might have the potential to become a future therapeutic target.

Objectives: Genetic screening can benefit early detection and intervention for hearing loss. The frequency of common deafness-associated variants in general populations is highly important for genetic screening and genetic counseling tailored to different ethnic backgrounds. We aimed to analyze the frequency of common deafness-associated variants in a large population-based Chinese newborn cohort and to explore the population-specific features in diverse populations worldwide., Design: This population-based cohort study analyzed the frequency of common deafness-associated variants in 3,555,336 newborns in the Chinese Newborn Concurrent Hearing and Genetic Screening cohort. Participants were newborn infants born between January 2007 and September 2020. Limited genetic screening for 20 variants in 4 common deafness-associated genes and newborn hearing screening were offered concurrently to all newborns in the Chinese Newborn Concurrent Hearing and Genetic Screening cohort. Sequence information of 141,456 individuals was also analyzed from seven ethnic populations from the Genome Aggregation Database for 20 common deafness-related variants. Statistical analysis was performed using R., Results: A total of 3,555,326 Chinese neonates completed the Newborn Concurrent Hearing and Genetic Screening were included for analysis. We reported the distinct landscape of common deafness-associated variants in this large population-based cohort. We found that the carrier frequencies of GJB2 , SLC26A4 , GJB3 , and MT-RNR were 2.53%, 2.05%, 0.37%, and 0.25%, respectively. Furthermore, GJB2 c.235delC was the most common variant with an allele frequency of 0.99% in the Chinese newborn population. We also demonstrated nine East-Asia-enriched variants, one Ashkenazi Jewish-enriched variant, and one European/American-enriched variant for hearing loss., Conclusions: We showed the distinct landscape of common deafness-associated variants in the Chinese newborn population and provided insights into population-specific features in diverse populations. These data can serve as a powerful resource for otolaryngologists and clinical geneticists to inform population-adjusted genetic screening programs for hearing loss., (Copyright © 2022 The Authors. Ear & Hearing is published on behalf of the American Auditory Society, by Wolters Kluwer Health, Inc.)

Genetic variants in GJB2 are the most frequent cause of congenital and childhood hearing loss worldwide. The purpose of this study was to delineate the genetic and phenotypic landscape of GJB2 SNV variants. All possible single-nucleotide substitution variants of the coding region of GJB2 (N = 2043) were manually curated following the ACMG/AMP hearing loss guidelines. As a result, 60 (2.9%), 177 (8.7%), 1499 (73.4%), 301 (14.7%) and 6 (0.3%) of the variants were classified as pathogenic, likely pathogenic, variant of uncertain significance, likely benign, and benign, respectively. 53% (84/158) of the pathogenic/likely pathogenic missense variants were not present in ClinVar. The second transmembrane domain and the 3 10 helix were highly enriched for pathogenic missense variants, while the intracellular loops were tolerant to variation. The N-terminal tail and the extracellular loop showed high clustering of variants that are associated with syndromic or dominant non-syndromic hearing loss. In conclusion, our study interpreted all possible single-nucleotide substitution coding variants, characterized novel clinically significant variants in GJB2, and revealed significant genotype-phenotype correlations at this common hearing loss locus. Our work provides a prototype for other genes with similarly high genetic and phenotypic heterogeneity., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hearing loss is one of the most genetically heterogeneous disorders known. Over 120 genes are reportedly associated with non-syndromic hearing loss (NSHL). To date, in Russia, there have been relatively few studies that apply massive parallel sequencing (MPS) methods to elucidate the genetic factors underlying non-GJB2-related hearing loss cases. The current study is intended to provide an understanding of the mutation spectrum in non-GJB2-related hearing loss in a cohort of Russian sensorineural NSHL patients and establish the best diagnostic algorithm. Genetic testing using an MPS panel, which included 33 NSHL and syndromic hearing loss (SHL) genes that might be misdiagnosed as NSHL genes, was completed on 226 sequentially accrued and unrelated patients. As a result, the molecular basis of deafness was found in 21% of the non-GJB2 NSHL cases. The total contribution pathogenic, and likely pathogenic, variants in the genes studied among all hereditary NSHL Russian patients was 12%. STRC pathogenic and likely pathogenic, variants accounted for 30% of diagnoses in GJB2-negative patients, providing the most common diagnosis. The majority of causative mutations in STRC involved large copy number variants (CNVs) (80%). Among the point mutations, the most common were c.11864G>A (p.Trp3955*) in the USH2A gene, c.2171&#95;2174delTTTG (p.Val724Glyfs*6) in the STRC gene, and c.107A>C (p.His36Pro) and c.1001G>T (p.Gly334Val) in the SLC26A4 gene. Pathogenic variants in genes involved in SHL accounted for almost half of the cases with an established molecular genetic diagnosis, which were 10% of the total cohort of patients with non-GJB2-related hearing loss.

Hereditary hearing loss is genetically heterogeneous, with diverse clinical manifestations. Here we performed targeted genome sequencing of 227 hearing loss related genes in 1027 patients with bilateral hearing loss and 520 healthy volunteers with normal hearing to comprehensively identify the molecular etiology of hereditary hearing loss in a large cohort from China. We obtained a diagnostic rate of 57.25% (588/1027) for the patients, while 4.67% (48/1027) of the patients were identified with uncertain diagnoses. Of the implicated 35 hearing loss genes, three common genes, including SLC26A4(278/588), GJB2(207/588), MT-RNR1(19/588), accounted for 85.54% (503/588) of the diagnosed cases, while 32 uncommon hearing loss genes, including MYO15A, MITF, OTOF, POU3F4, PTPN11, etc. accounted for the remaining diagnostic rate of 14.46% (85/588). Apart from Pendred syndrome, other eight types of syndromic hearing loss were also identified. Of the 64 uncertain significant variants and 244 pathogenic/likely pathogenic variants identified in the patients, 129 novel variants were also detected. Thus, the molecular etiology presented with high heterogeneity with the leading causes to be SLC26A4 and GJB2 genes in the Chinese hearing loss population. It's urgent to develop a database of the ethnicity-matched healthy population as well as to perform functional studies for further classification of uncertain significant variants., (© 2022. The Author(s).)

Background: Hearing loss (HL) is a heterogeneous condition that causes partial or complete hearing impairment. Hundreds of variants in >60 genes have been reported to be associated with Hereditary HL (HHL), variants of the GJB2 gene are the most common cause of congenital SNHL, with >100 variants reported. The HHL prevalence is thought to be high in the Arab population; however, the genetic epidemiology of HHL among Emirati populations is understudied., Aims: To shed light on the mutational spectrum of NSHL in Emirati patients seen in the genetic clinic over 10 years and to capture founder mutation(s) if any were identified., Methods: Retrospective chart review of all Emirati patients assessed by clinical geneticists due to NSHL during the period between January 2010 to December 2020. Genetic tests were done based on clinical phenotypes of the patient and family history including targeted mutation testing, next-generation sequencing, or whole-exome sequencing (solo or trio). The authors did literature reviews using PubMed for all previously reported articles related to NSHL genes from UAE., Results: A total of 162 patients with HL, were evaluated during the period between January 2010 to December 2020. There were 82 patients with NSHL, and only 72 patients who completed the genetic evaluations were included in this retrospective study. Among the studied group, 42 (51.2%) were males and 40 (48.78%) were females. The youngest patient was 2 years old and the oldest patient was 50 years old. Consanguinity was documented in 76 patients (92.68%). A total of 14 mutations reported here are novel (23/72 i.e., 31.9%). Twelve missense mutations, 6 nonsense mutations, 6 frameshift mutations, 2 in-frame deletion mutations, and 1 splice site mutation was found. Variants in the GJB2 gene are the most commonly identified cause of NSHL, with c.35delG being the most followed by c.506G > A. The second commonly found variant is c.934C > G (p.Arg312Gly) in the CDC14A gene, found in 9 patients. This was followed by variants in OTOF and SLC26A4 genes, found in 8 patients, respectively. Chromosomal microdeletions encompassing genes causing NSHL were found in 3 patients. No mitochondrial mutations were found in this study group. A total of 11 previous reports about Emirati patients with NSHL were reviewed, with a total of 35 patients., Conclusion: Emirati patients with NSHL have several mutations, most notably missense mutations. Novel mutations are worth further testing and represent the area for future researches., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Objective: To examine etiology, comorbidities, and health service use in a cohort of children with permanent hearing loss. Receiving an etiological diagnosis can inform reproductive planning, rehabilitation outcomes, predict additional disabilities, and direct intervention or management decisions., Design: Retrospective audit of 518 deaf/hard-of-hearing children attending a tertiary pediatric outpatient clinic (2016-2019) using descriptive statistics. We used linear regression to investigate the relationship between degree of hearing loss, comorbidities, and health service use., Results: Of the 518 children who attended the clinic, 481 (92.9%) proceeded with testing for etiology. Most children (399/518, 77.0%) were diagnosed with hearing loss by 3 mo of age. Of the children tested, the cause of hearing loss was confirmed in 234/481 (48.6%), suspected in 113/481 (23.5%), and unknown in 134/481 (27.9%); 17/341 (5.0%) had congenital cytomegalovirus (CMV), 17/320 (5.3%) had enlarged vestibular aqueducts, 67/213 (31.5%) of children with bilateral hearing loss had connexin mutation, and 25/72 (34.7%) of children with unilateral loss had hypoplastic/absent cochlear nerve on imaging. The odds of having a definitive/suspected diagnosis were twice as likely for indivduals with profound hearing loss than mild hearing loss (OR 2.1; 95% CI, 1.2-3.9; P = 0.02). The majority (348/518, 67.2%) of children had medical comorbidities, and most children attended otolaryngology (453/518, 87.5%), early intervention (358/518, 69.1%), and genetic (287/518, 55.4%) services., Conclusions: Children with hearing loss have diverse etiologies, most have comorbidities, and attend multiple services. Most families elected to proceed with diagnostic testing for etiology. Current guidelines and expanded access to genetic testing identified a confirmed/suspected etiological diagnosis in 72.1% of children tested. The number of comorbidities correlated with service use, regardless of hearing loss severity., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Genetic testing is widely used in diagnosing genetic hearing loss in patients. Other than providing genetic etiology, the benefits of genetic testing in pediatric patients with hearing loss are less investigated., Methods: From 2018-2020, pediatric patients who initially presented isolated hearing loss were enrolled. Comprehensive genetic testing, including GJB2/SLC26A4 multiplex amplicon sequencing, STRC/OTOA copy number variation analysis, and exome sequencing, were hierarchically offered. Clinical follow-up and examinations were performed., Results: A total of 80 pediatric patients who initially presented isolated hearing loss were considered as nonsyndromic hearing loss and enrolled in this study. The definitive diagnosis yield was 66% (53/80) and the likely diagnosis yield was 8% (6/80) through comprehensive genetic testing. With the aid of genetic testing and further clinical follow-up and examinations, the clinical diagnoses and medical management were altered in eleven patients (19%, 11/59); five were syndromic hearing loss; six were nonsyndromic hearing loss mimics., Conclusion: Syndromic hearing loss and nonsyndromic hearing loss mimics are common in pediatric patients who initially present with isolated hearing loss. The comprehensive genetic testing provides not only a high diagnostic yield but also valuable information for clinicians to uncover subclinical or pre-symptomatic phenotypes, which allows early diagnosis of SHL, and leads to precise genetic counseling and changes the medical management., (© 2022. The Author(s).)

Background: Deafness is the most prevalent human sensorineural defect. It may occur as a result of an external auditory canal involvement, or a deficiency in the sound conduction mechanism, or an impairment of the cochlea, the cochlear nerve or central auditory perception. The genetic causes are the most common, as approximately 70% of hearing disorders are of hereditary origin, divided into two groups, syndromic (associated with other symptoms) and no syndromic (isolated deafness)., Methods: A whole exome sequencing was performed to identify the genetic cause of hearing loss in six Moroccan families and Sanger sequencing was used to validate mutations in these genes., The Results: The results of four out of the six families revealed four genetic variants in the genes GJB2, COL4A3, ATP6V1B1 and EDNRB responsible for non-syndromic and syndromic hearing loss. Multiple Bioinformatics programs and molecular modelling predicted the pathogenic effect of these mutations., Conclusions: We identified in Moroccan deaf patients four homozygous mutations. These results show the importance of whole exome sequencing to identify pathogenic mutations in heterogeneous disorders with multiple genes responsible., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Approximately 14.5 million Pakistani individuals have a hearing loss and half of these cases may be due to genetic causes. Though significant progress has been made in uncovering genetic variants for recessively inherited nonsyndromic deafness, Pendred syndrome, and Usher syndromes, the same is not true for dominantly inherited hearing loss, most syndromic cases and deafness with complex inheritance patterns. Variants of 57 genes have been reported to cause nonsyndromic recessive deafness in Pakistan, though most are rare. Variants of just five genes GJB2, HGF, MYO7A, SLC26A4, and TMC1 together explain 57% of profound deafness while those of GJB2, MYO15A, OTOF, SLC26A4, TMC1, and TMPRSS3 account for 47% of moderate to severe hearing loss. In contrast, although variants of at least 39 genes have been implicated in different deafness syndromes, their prevalence in the population and the spectrum of mutations have not been explored. Furthermore, research on genetics of deafness has mostly focused on individuals from the Punjab province and needs to be extended to other regions of Pakistan. Identifying the genes and their variants causing deafness in all ethnic groups is important as it will pinpoint rare as well as recurrent mutations. This information may ultimately help in offering genetic counseling and future treatments., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: This study aimed to quantitatively assess the incidence of hearing loss in relation to age in individuals with biallelic p.V37I variant in GJB2., Methods: Population screening of the biallelic p.V37I variant was performed in 30,122 individuals aged between 0 and 97 years in Shanghai. Hearing thresholds of the biallelic p.V37I individuals and the controls were determined by click auditory brainstem response or pure tone audiometry., Results: Biallelic p.V37I was detected in 0.528% (159/30,122) of the subjects. Of the biallelic p.V37I newborns, 43.91% (18/41) passed their distortion-product otoacoustic emissions-based newborn hearing screening or had hearing thresholds lower than 20 decible above normal hearing level. The older newborns had elevated hearing thresholds, with increasing incidence of 9.52%, 23.08%, 59.38%, and 80.00% for moderate or higher grade of hearing loss in age groups of 7 to 15 years, 20 to 40 years, 40 to 60 years, and 60 to 85 years, respectively. Their hearing deteriorated at a rate of 0.40 dB hearing level per year on average; males were more susceptible, and deterioration occurred preferentially at higher sound frequencies., Conclusion: The biallelic p.V37I variant is associated with steadily progressive hearing loss with increasing incidence over the course of life. Most of the biallelic p.V37I individuals may develop significant hearing loss in adulthood and, can benefit from early diagnosis and intervention through wide-spread genetic screening., Competing Interests: Conflict of Interest The authors declare no conflicts of interest. The authors declare that they do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Prevalence and locus/allelic heterogeneity of the hereditary hearing loss (HL) vary significantly in different human populations. Investigation of the hereditary HL diversity and the evaluation of the factors determining the region-specific landscapes of genetic HL are important for local healthcare and medical genetic services. This review presents the summarized data from the published studies concerning the genetic etiology of HL in different populations of Russia. Multiethnic population of Russia (in total, about 146 million on 2021) includes over 180 different ethnic groups, the number of which varies from millions to just several thousand people. Among them, Russians are the largest group (about 111 million). The contribution of GJB2 gene in the HL etiology in patients of different ethnicities and ethnic-specific prevalence of the GJB2 pathogenic variants were studied in many local populations of Russia. However, the investigation of other "deafness" genes is still limited to a relatively small number of studies on patients with HL of unsolved etiology., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hearing loss is one of the most common sensory defects, affecting 5.5% of the worldwide population and significantly impacting health and social life. It is mainly attributed to genetic causes, but their relative contribution reflects the geographical region's socio-economic development. Extreme genetic heterogeneity with hundreds of deafness genes involved poses challenges for molecular diagnosis. Here we report the investigation of 542 hearing-impaired subjects from all Brazilian regions to search for genetic causes. Biallelic GJB2/GJB6 causative variants were identified in 12.9% (the lowest frequency was found in the Northern region, 7.7%), 0.4% carried GJB2 dominant variants, and 0.6% had the m.1555A > G variant (one aminoglycoside-related). In addition, other genetic screenings, employed in selected probands according to clinical presentation and presumptive inheritance patterns, identified causative variants in 2.4%. Ear malformations and auditory neuropathy were diagnosed in 10.8% and 3.5% of probands, respectively. In 3.8% of prelingual/perilingual cases, Waardenburg syndrome was clinically diagnosed, and in 71.4%, these diagnoses were confirmed with pathogenic variants revealed; seven out of them were novel, including one CNV. All these genetic screening strategies revealed causative variants in 16.2% of the cases. Based on causative variants in the molecular diagnosis and genealogy analyses, a probable genetic etiology was found in ~ 50% of the cases. The present study highlights the relevance of GJB2/GJB6 as a cause of hearing loss in all Brazilian regions and the importance of screening unselected samples for estimating frequencies. Moreover, when a comprehensive screening is not available, molecular diagnosis can be enhanced by selecting probands for specific screenings., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Latin America comprises all countries from South and Central America, in addition to Mexico. It is characterized by a complex mosaic of regions with heterogeneous genetic profiles regarding the geographical origin of the ancestors and proportions of admixture between the Native American, European and African components. In the first years following the findings of the role of the GJB2/GJB6 genes in the etiology of hearing loss, most scientific investigations about the genetics of hearing loss in Latin America focused on assessing the frequencies of pathogenic variants in these genes. More recently, modern techniques allowed researchers in Latin America to make exciting contributions to the finding of new candidate genes, novel mechanisms of inheritance in previously known genes, and characterize a wide diversity of variants, many of them unique to Latin America. This review aimed to provide a general landscape of the genetic studies about non-syndromic hearing loss in Latin America and their main scientific contributions. It allows the conclusion that, although there are similar contributions of some genes, such as GJB2/GJB6, when compared to European and North American countries, Latin American populations revealed some peculiarities that indicate the need for tailored strategies of screening and diagnosis to specific geographic regions., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To examine the expression of tight-junction connexin ZO-1 in the stria vascularis tissue of the cochlea by using spontaneous endolymphatic hydrops animal model constructed with PHEX gene mutant mice, and to analyze the dynamic changes of the gene mutant mice in pathology, imaging, and hearing function., Methods: Male Hyp-Duk/Y mice with PHEX gene mutation were selected as the experimental group at three time points, 21 days post birth (P21), 90 days post birth (P90) and 120 days post birth (P120), and wild-type male mice of the same ages were selected as the control groups. The cochlear sections were HE-stained in order to observe whether endolymphatic hydrops was present or absent and to assess its severity. The expression of connexin ZO-1 in both groups was evaluated through immunohistochemical staining of cochlear sections. Auditory-evoked brainstem response (ABR) was induced in both groups at P90 and gadolinium-enhanced MRI was conducted in vivo to observe the middle-order endolymphatic dilatation of cochlea in experimental and control mice aged P21, P90 and P120., Results: HE staining of pathological sections of PHEX Hyp-Duk/Y mice aged P90 and P120 showed increased endolymphatic hydronephrosis. The level of striae ZO-1 in PHEX Hyp-Duk/Y mice aged P90 and P120 was significantly lower than that of the controls of the same age ( P <0.05). The expression level of ZO-1 was significantly negatively correlated with the degree of endolymphatic hydronephrosis ( r =-0.939, P <0.01). The bilateral ABR threshold of PHEX Hyp-Duk/Y mice aged P90 was higher than that of the wild-type mice of the same age, and the mutant mice showed asymmetric hearing loss on both sides. Severe endolymphatic hydronephrosis was observed in PHEX Hyp-Duk/Y mice aged P90 and P120 through in vivo MRI gadolinium imaging., Conclusion: PHEX Hyp-Duk/Y can be used as a sound model for basic research of Ménière's disease. Compared with wild-type mice, PHEX Hyp-Duk/Y mice showed decreased expression of connexin protein ZO-1, which damaged the function of the blood-labyrinth barrier in stria vascularis, and was involved in the formation of endolymphatic hydrops. 7.0 T MRI gadolinium imaging can be used to observe the changes of severe endolymphatic hydrops in mice in vivo , providing imaging basis for the diagnosis of Ménière's disease., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)

Hereditary hearing loss is one of the most common human neurosensory disorders, and there is a great need for early intervention methods such as genetically screening newborns. Single nucleotide polymorphisms (SNPs) are the major genetic targets for hearing-loss screening. In this study, a fully integrated SNP genotyping system was constructed to identify hereditary hearing loss-related genetic markers from human whole blood. The entire detection process, including blood cell lysis, nucleic acid extraction, the reaction mixture distribution, the chambers sealing and the two-colour multiplex competitive allele-specific polymerase chain reaction (KASP), can be automatically conducted in a self-contained cassette within 3 hours. To critically evaluate the performance of the system, its specificity, sensitivity and stability were assessed. Then, 13 clinical samples were genotyped with this fluidic cassette system to detect seven hotspot deafness-associated mutations in three genes ( MT-RNR1 , GJB2 and SLC26A4 ). The detection results of the cassette system were 100% concordant with those obtained by Sanger sequencing, proving its accuracy in the genetic screening of inherited hearing loss.

Background: Hereditary hearing loss (HHL) is a common heterogeneous disorder affecting all ages, ethnicities, and genders. The most common form of HHL is autosomal recessive non-syndromic hearing loss (ARNSHL), in which there is no genotype-phenotype correlation in the majority of cases. This study aimed to identify the genetic causes of hearing loss (HL) in a family with Iranian Azeri Turkish ethnicity negative for gap junction beta-2 (GJB2), gap junction beta-6 (GJB6), and mitochondrially encoded 12S rRNA (MT-RNR1) deleterious mutations., Methods: Targeted genome sequencing method was applied to detect genetic causes of HL in the family. Sanger sequencing was employed to verify the segregation of the variant. Finally, we used bioinformatics tools and American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines to determine whether the detected variant might affect the corresponding protein or not., Results: A novel homozygous missense mutation, c.499G>A (p.G167R), was identified in exon 5 of the ESRRB (estrogen-related receptor beta) gene. Healthy and affected family members confirmed the co-segregation of the variant with ARNSHL. Eventually, the variant's pathogenicity was confirmed by the in silico analysis and the ACMG/AMP guidelines., Conclusion: The study suggests that the detected variant, c.499G>A, plays a crucial role in the development of ARNSHL, emphasizing the clinical significance of the ESRRB gene in ARNSHL patients. Additionally, it would be helpful for genetic counseling and clinical management of ARNSHL patients and providing preventive opportunities., (© 2022. The Author(s).)

Hearing loss is the most frequent sensory disorder, with an incidence of 1:1500 live newborns. In more than 50% of patients, it is associated with a genetic cause, while in up to 30% of cases, it is related to syndromic entities. We performed a literature review of studies on congenital hearing loss of genetic origin in the Mexican population. We identified eight reports that showed that the pathogenic variants most frequently associated with hearing loss are related to the GJB2 gene, although in a low percentage (3%). Other mutations were identified in the GJB6, SLC26A4, or CHD23 genes. On this basis, a possible diagnostic strategy in Mexican patients with hearing loss is to consider an initial screening of these three genes. If these genes were negative for pathogenic variants, the following steps would be to consider second-generation sequencing analysis focused on panels of genes associated with hearing loss, isolated or syndromic, and if necessary, to perform exome or whole-genome analysis. Establishing an etiologic cause is critical in clinically evaluating patients with congenital hearing loss and their families. It can help determine rehabilitation strategies, such as hearing aids or cochlear implants and provide information on disease progression and genetic counseling in this population., (Copyright: © 2022 Permanyer.)

Genetic variants in the GJB2 gene which encodes for the Connexin 26 protein account for ∼ 60% of cases of genetic hearing loss. A novel hiPSC line was generated from an individual with the hearing loss-related variant c.109G > A in GJB2 leading to the p.V37I alteration in the Connexin26 protein. These cells will help to delineate the role of GJB2 in hearing loss pathogenesis and serve as a platform for drug discovery and development., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To detect common pathogenic variants associated with congenital deafness among neonates from Huizhou and surrounding areas and discuss its implications., Methods: Thirteen hot-spot mutations in four most common pathogenic genes were screened among 20 934 neonates from March 2017 to December 2019., Results: In total 760 neonates were found to carry common pathogenic variants (3.63%). Sixty two neonates have carried homozygous/compound heterozygous variants or homoplasmy/heteroplasmy mutations of mtDNA (0.29%). Further analysis of five abnormal cases revealed that 3 of them have carried compound heterozygous mutations of GJB2 gene, and 2 were due to compound heterozygous variants of the CDH23 gene., Conclusion: Genetic testing has a great clinical significance for the prevention and reduction of congenital hearing loss, but the scope needs to be updated and redefined by removing mutation sites with a very low rate, adding new significant sites, and improvement of the technical strategies.

Deafness is a total or partial hearing loss that may appear at any age and with different degrees of severity. Approximately 50% of hearing loss have a genetic origin, and among them, non-syndromic sensorineural deafness represents about 70% of the cases. From them, 80% correspond to autosomal recessive inheritance deafness. Autosomal recessive deafness was not studied enough at the molecular level in Iraq. This study aimed to verify the frequency of three GJB2 mutations in non-syndromic sensorineural deafness in the Iraqi population. The current case-control study was conducted from January 2018 to January 2020. The study included 95 deafness patients (55 males and 40 females) and 110 healthy control group. Age and sex were matched between the two groups. In order to detect c.35delG, 235delC, and 167delT mutations in the GJB2 gene, we employed the PCR-RFLP technique. The c.35delG was the main frequent mutation encountered with the GJB2 gene among patients with autosomal recessive non-syndromic sensorineural hearing loss. Among them, 35 (36.8%) were homozygous, 40 (42.1%) were heterozygous, and 20 (21.1%) were wild genotypes. The second-degree mutation in the GJB2 gene was c.235delC mutation, which from the 95 deaf patients, there were 20 (21.1%) with homozygous, 33 (34.7%) heterozygous, and 42 (44.2%) wild genotypes. None of the 95 deaf patients showed the c.167delT mutation, and no mutations appeared in the control group. Our data concluded that the GJB2 c.35delG and c.235delC gene mutations were the main cause of autosomal recessive non-syndromic sensorineural hearing loss in the Iraqi deaf population., (©2021 JOURNAL of MEDICINE and LIFE.)

The gap junction beta-2 (GJB2) gene is the most common genetic cause of hereditary deafness worldwide. Among them, the G45E/Y136X mutation in GJB2 is the third most prevalent in Japan. In this study, we generated two induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of siblings with moderate-to-severe hearing loss (patient) or normal hearing (genetic carrier) carrying a homozygous or heterozygous G45E/Y136X mutation in GJB2 gene, respectively. These iPSC lines showed the expression of pluripotency markers and could differentiate into three germ layers. These disease-specific iPSC lines will be a powerful tool for investigating the pathogenesis of GJB2-related deafness., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Abstract: To understand the possible carrier status of genes associated with hereditary hearing loss (HHL) in the general population among local residents and to give genetic counseling for pregnant women.A total of 3541 subjects were recruited. We used multiplex PCR technology combined with next-generation sequencing technology to detect 100 hotspot mutations in 18 common deafness-related genes. The homozygous mutation screening results were verified using Sanger sequencing.Of the 3541 participants, 37 alleles of 8 deafness genes were detected. A total of 145 (4.09%) were found to be GJB2 gene mutation carriers, and the hotspot mutation was c.235delC (1.54%). Twenty three (0.65%) were found to be GJB3 gene mutation carriers. A total of 132 (3.37%) were found to be SLC26A4 gene mutation carriers, and the hotspot mutation was c.919-2A > G (0.49%). Forty four (1.24%) were found to be mitochondrial DNA mutation carriers. Sanger sequencing results verified that 2 cases were homozygous for the c.235delC mutation and that 1 case was homozygous for the c.754T > C mutation.Genetic testing for pregnant women and their partners allows early identification of the molecular etiology of hearing loss (HL). On the one hand, it could give genetic counseling for pregnant women, such as early diagnosis of delayed deafness and drug-susceptible deafness. On the other hand, it could be used to assess hearing conditions during pregnancy, leading to prevention and timely intervention for newborns., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Mutation in the gap junction beta-2 (GJB2) gene is a main cause of autosomal-recessive nonsyndromic hearing loss (ARNSHL). The c.235delC and c.299-300del mutations are more common mutations in Chinese Han deaf patients, in which the compound heterozygous mutations of these two sites cause severe-to-profound hearing loss in a significant percentage. We established an induced pluripotent stem cell (iPSC) line from a 2-year-old boy with hearing loss, caused by compound heterozygous mutations in GJB2 (c.235delC and c.299-300del). The iPSCs was verified based on pluripotency markers and demonstrated trilineage differentiation potential in vitro., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Congenital hearing loss is one of the most common birth defects. Early identification and management play a crucial role in improving patients' communication and language acquisition. Previous studies demonstrated that genetic screening complements newborn hearing screening in clinical settings., Methods: We developed a multiplex PCR amplicon sequencing assay to sequence the full coding region of the GJB2 gene, the most pathogenic variants of the SLC26A4 gene, and hotspot variants in the MT-RNR1 gene. The sensitivity, specificity, and reliability were validated via samples with known genotypes. Finally, a pilot study was performed on 300 anonymous dried blood samples., Results: Of 103 samples with known genotypes, the multiplex PCR amplicon sequencing assay accurately identified all the variants, demonstrating a 100% sensitivity and specificity. The consistency is high in the analysis of the test-retest reliability and internal consistency reliability. In the pilot study, 12.3% (37/300) of the newborns were found to carry at least one pathogenic variant, including 24, 10, and 3 from the GJB2, SLC26A4, and MT-RNR1 gene, respectively. With an allele frequency of 2.2%, the NM&#95;004004.6(GJB2):c.109G>A was the most prevalent variant in the study population., Conclusion: The multiplex PCR amplicon sequencing assay is an accurate and reliable test to detect hearing loss variants in the GJB2, SLC26A4, and MT-RNR1 genes. It can be used to screen genetic hearing loss in newborns.

Mutations in connexin 30 (Cx30) are known to cause severe congenital hearing impairment; however, the mechanism by which Cx30 mediates homeostasis of endocochlear gap junctions is unclear. We used a gene deletion mouse model to explore the mechanisms of Cx30 in preventing hearing loss. Our results suggest that despite severe loss of the auditory brain-stem response and endocochlear potential at postnatal day 18 , Cx30 -/- mice only show sporadic loss of the outer hair cells. This inconsistency in the time course and severity of hearing and hair cell losses in Cx30 -/- mice might be explained, in part, by an increase in reactive oxygen species generation beginning at postnatal day 10 . The expression of oxidative stress genes was increased in Cx30 -/- mice in the stria vascularis, spiral ligament, and organ of Corti. Furthermore, Cx30 deficiency caused mitochondrial dysfunction at postnatal day 18 , as assessed by decreased ATP levels and decreased expression of mitochondrial complex I proteins, especially in the stria vascularis. Proteomic analysis further identified 444 proteins that were dysregulated in Cx30 -/- mice, including several that are involved in mitochondria electron transport, ATP synthesis, or ion transport. Additionally, proapoptotic proteins, including Bax, Bad, and caspase-3, were upregulated at postnatal day 18 , providing a molecular basis to explain the loss of hearing that occurs before hair cell loss. Therefore, our results are consistent with an environment of oxidative stress and mitochondrial damage in the cochlea of Cx30 -/- mice that is coincident with hearing loss but precedes hair cell loss.