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BACKGROUND: A structural heart disease or functional electrical abnormalities can cause an electrical storm. Case presentation: We present a young boy with an electrical storm who had no cardiac risk factors and a positive family history of sudden cardiac death. The stepwise diagnostic approach was ineffective in determining previously known causes as the origin of the electrical storm. However, whole-exome sequencing (with Next Generation Illumina Sequencing) revealed a mutation in the GJB2 (NM_004004:exon2:c.G71A:p.W24X) gene. CONCLUSION: A mutation in the GJB2 gene, which forms the connexin 26 protein, a crucial component of the myocytes’ intercalated disc of gap junction complex between the myocytes, results in an abnormal electrical cell-by-cell conductance, and, eventually, ventricular storm. General anesthesia was used to control the storm, and intracardiac pacing was fruitful in ceasing the subsequent VT storms. [ABSTRACT FROM AUTHOR]

Background: Hearing loss (HL) is an impairment of auditory function with identified genetic forms that can be syndromic (30%) or non-syndromic (70%). HL is genetically heterogeneous, with more than 1,000 variants across 150 causative genes identified to date. The genetic diagnostic rate varies significantly depending on the population being tested. Countries with a considerably high rate of consanguinity provide a unique resource for studying rare forms of recessive HL. In this study, we identified genetic variants associated with bilateral sensorineural HL (SNHL) using whole-exome sequencing (WES) in 11 families residing in the United Arab Emirates (UAE). Results:We established the molecular diagnosis in six probands, with six different pathogenic or likely pathogenic variants in the genes MYO15A, SLC26A4, and GJB2. One novel nonsense variant, MYO15A:p.Tyr1962Ter*, was identified in a homozygous state in one family, which has not been reported in any public database. SLC26A4 and GJB2 were found to be the most frequently associated genes in this study. In addition, six variants of uncertain significance (VUS) were detected in five probands in the genes CDH23, COL11A1, ADGRV1, NLRP3, and GDF6. In total, 12 variants were observed in eight genes. Among these variants, eight missense variants (66.7%), three nonsense variants (25.0%), and one frameshift (8.3%) were identified. The overall diagnostic rate of this study was 54.5%. Approximately 45.5% of the patients in this study came from consanguineous families. Conclusion: Understanding the genetic basis of HL provides insight for the clinical diagnosis of hearing impairment cases through the utilization of nextgeneration sequencing (NGS). Our findings contribute to the knowledge of the heterogeneous genetic profile of HL, especially in a population with a high rate of consanguineous marriage in the Arab population. [ABSTRACT FROM AUTHOR]

Background: Hearing loss (HL) is an impairment of auditory function with identified genetic forms that can be syndromic (30%) or non-syndromic (70%). HL is genetically heterogeneous, with more than 1,000 variants across 150 causative genes identified to date. The genetic diagnostic rate varies significantly depending on the population being tested. Countries with a considerably high rate of consanguinity provide a unique resource for studying rare forms of recessive HL. In this study, we identified genetic variants associated with bilateral sensorineural HL (SNHL) using whole-exome sequencing (WES) in 11 families residing in the United Arab Emirates (UAE).Results: We established the molecular diagnosis in six probands, with six different pathogenic or likely pathogenic variants in the genes MYO15A, SLC26A4, and GJB2. One novel nonsense variant, MYO15A:p.Tyr1962Ter*, was identified in a homozygous state in one family, which has not been reported in any public database. SLC26A4 and GJB2 were found to be the most frequently associated genes in this study. In addition, six variants of uncertain significance (VUS) were detected in five probands in the genes CDH23, COL11A1, ADGRV1, NLRP3, and GDF6. In total, 12 variants were observed in eight genes. Among these variants, eight missense variants (66.7%), three nonsense variants (25.0%), and one frameshift (8.3%) were identified. The overall diagnostic rate of this study was 54.5%. Approximately 45.5% of the patients in this study came from consanguineous families.Conclusion: Understanding the genetic basis of HL provides insight for the clinical diagnosis of hearing impairment cases through the utilization of next-generation sequencing (NGS). Our findings contribute to the knowledge of the heterogeneous genetic profile of HL, especially in a population with a high rate of consanguineous marriage in the Arab population.

Objective To analyze the mutation characteristics of GJB2 gene in 799 neonates in Pu ′er region of Yunnan province.Methods The GJB2 gene coding region was detected in 799 neonatal heel blood samples by polymerase chain reaction-base sequence direct sequencing method, and gene polymorphism distribution, genotype frequency and allele frequency were analyzed.Hardy-Weinberg equilibrium, hahatype and linkage disequilibrium were analyzed by Arlerquin3.11 software.Results c.79G＞A,c.109G＞A,c.341A＞G,c.299-300delAT,c.235delC,c.608T＞C,c.226C＞A,c.571T＞C,c.512insAACG,c.550C＞T,c.180C＞G,and c.368C＞A were detected in exon 2 of GJB2 gene in 799 neonatal samples.According to statistics, the total mutation carrier rate was 60.83%,among which, the mutation carrier rates of c.79G＞A,c.341A＞G,c.109G＞A and c.608T＞C were 46.06%,36.30%,13.89% and 4.51%,respectively, and the mutation carrying rate of other sites was less than 1.00%.The polymorphic mutations of these 12 genes were consistent with Hardy-Weinberg equilibrium law, and there were 22 hahatypes in total.The linkage disequilibrium analysis showed that there were significant linkage disequilibria at two loci: c.79G＞A and c.341A＞G (D′=0.987 4,r~2=0.674 0) .Conclusion There are abundant mutation types and frequency of GJB2 gene in newborns in Pu ′er region of Yunnan province, and the total mutation carrying rate is high, which provides support for clinical detection and genetic counseling. [ABSTRACT FROM AUTHOR]

Background & aim: Deafness (HL) is the most common sensorineural disorder. The frequency of hearing impairment in the world is one in every 500 newborns. However, in Iran, due to the high rate of consanguineous marriages, this amount is estimated to be two to three times higher. So far, more than 120 genes causing non-syndromic deafness (NSHL) have been known in the world. Among these, GJB2 gene mutations are the most common cause of autosomal recessive NSHL. The aim of this research was to determine and investigate the frequency and spectrum of GJB2 gene mutations in the non-syndromic deaf population of Semnan province. Methods: The present practical study was conducted in 2021 on 50 patients with non-syndromic hearing loss from 50 unrelated families. First, the very common 35delG mutation was screened by allele-specific polymerase chain reaction (ASPCR). Then, in order to identify other mutations of the GJB2 gene, patients who were negative or heterozygous for the 35delG mutation were analyzed by trench sequencing for all exonic regions and splicing sites of the GJB2 gene. The collected data were analyzed using descriptive statistical tests. Results: In the present study, 100 chromosomes (50 patients) were examined. 12 chromosomes (12%) indicated mutation in GJB2 gene. Among these, the share of each of the identified mutations 35delG, IVS1+1G>A and c.94C>T: p. Arg32Cys in the deaf population of Semnan province, respectively; 7, 4 and 1 percent. Thus, the common 35delG mutation includes 58.34% of all identified mutations. Also, unlike other populations studied in Iran, the IVS1+1G>A splice site mutation had a relatively high prevalence in the deaf population of Semnan province. Conclusion: The results of the present study indicated that GJB2 gene mutations comprised only 12% of mutations causing hearing loss in the deaf population of Semnan province, which emphasizes the importance of using next generation sequencing techniques to identify other genes causing hereditary hearing loss in this population. Such an approach will significantly aid in carrying out genetic counseling, prenatal diagnosis and clinical management of hearing loss in Semnan province.

Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital ectodermal dysplastic syndrome presenting with keratitis, ichthyosis and sensorineural hearing loss. The most common causes of KID syndrome are heterozygous missense mutations in the GJB2 gene that codes for connexin 26.

Background & aim: Deafness (HL) is the most common sensorineural disorder. The frequency of hearing impairment in the world is one in every 500 newborns. However, in Iran, due to the high rate of consanguineous marriages, this amount is estimated to be two to three times higher. So far, more than 120 genes causing non-syndromic deafness (NSHL) have been known in the world. Among these, GJB2 gene mutations are the most common cause of autosomal recessive NSHL. The aim of this research was to determine and investigate the frequency and spectrum of GJB2 gene mutations in the non-syndromic deaf population of Semnan province. Methods: The present practical study was conducted in 2021 on 50 patients with non-syndromic hearing loss from 50 unrelated families. First, the very common 35delG mutation was screened by allele-specific polymerase chain reaction (ASPCR). Then, in order to identify other mutations of the GJB2 gene, patients who were negative or heterozygous for the 35delG mutation were analyzed by trench sequencing for all exonic regions and splicing sites of the GJB2 gene. The collected data were analyzed using descriptive statistical tests. Results: In the present study, 100 chromosomes (50 patients) were examined. 12 chromosomes (12%) indicated mutation in GJB2 gene. Among these, the share of each of the identified mutations 35delG, IVS1+1G>A and c.94C>T: p. Arg32Cys in the deaf population of Semnan province, respectively; 7, 4 and 1 percent. Thus, the common 35delG mutation includes 58.34% of all identified mutations. Also, unlike other populations studied in Iran, the IVS1+1G>A splice site mutation had a relatively high prevalence in the deaf population of Semnan province. Conclusion: The results of the present study indicated that GJB2 gene mutations comprised only 12% of mutations causing hearing loss in the deaf population of Semnan province, which emphasizes the importance of using next generation sequencing techniques to identify other genes causing hereditary hearing loss in this population. Such an approach will significantly aid in carrying out genetic counseling, prenatal diagnosis and clinical management of hearing loss in Semnan province.

Hearing loss is the most common congenital sensory impairment. Mutations or deficiencies of the GJB2 gene are the most common genetic cause of congenital non-syndromic deafness. Pathological changes such as decreased potential in the cochlea, active cochlear amplification disorders, cochlear developmental disorders and macrophage activation have been observed in various GJB2 transgenic mouse models. In the past, researchers generally believed that the pathological mechanisms underlying GJB2-related hearing loss comprised a K+ circulation defect and abnormal ATP-Ca2+ signals. However, recent studies have shown that K+ circulation is rarely associated with the pathological process of GJB2-related hearing loss, while cochlear developmental disorders and oxidative stress play an important, even critical, role in the occurrence of GJB2- related hearing loss. Nevertheless, these research has not been systematically summarized. In this review, we summarize the pathological mechanisms of GJB2- related hearing loss, including aspects of K+ circulation, developmental disorders of the organ of Corti, nutrition delivery, oxidative stress and ATP-Ca2+ signals. Clarifying the pathological mechanism of GJB2-related hearing loss can help develop new prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

The GJB2 (Cx26) gene pathogenic variants are associated with autosomal recessive deafness type 1A (DFNB1A, OMIM #220290). Direct sequencing of the GJB2 gene among 165 hearing-impaired individuals living in the Baikal Lake region of Russia identified 14 allelic variants: pathogenic/likely pathogenic—nine variants, benign—three variants, unclassified—one variant, and one novel variant. The contribution of the GJB2 gene variants to the etiology of hearing impairment (HI) in the total sample of patients was 15.8% (26 out of 165) and significantly differed in patients of different ethnicity (5.1% in Buryat patients and 28.9% in Russian patients). In patients with DFNB1A (n = 26), HIs were congenital/early onset (92.3%), symmetric (88.5%), sensorineural (100.0%), and variable in severity (moderate—11.6%, severe—26.9% or profound—61.5%). The reconstruction of the SNP haplotypes with three frequent GJB2 pathogenic variants (c.-23+1G>A, c.35delG or c.235delC), in comparison with previously published data, supports a major role of the founder effect in the expansion of the c.-23+1G>A and c.35delG variants around the world. Comparative analysis of the haplotypes with c.235delC revealed one major haplotype G A C T (97.5%) in Eastern Asians (Chinese, Japanese and Korean patients) and two haplotypes, G A C T (71.4%) and G A C C (28.6%), in Northern Asians (Altaians, Buryats and Mongols). The variable structure of the c.235delC-haplotypes in Northern Asians requires more studies to expand our knowledge about the origin of this pathogenic variant. [ABSTRACT FROM AUTHOR]

Abstract Background Noise, a physical factor in most work environments, has many effects on human health. Exposure to excessive noise can modify the expression of associated genes with NIHL. The aim of this study to elucidate changes in expression of GJB2 and SLC26A4 after exposure to intense noise which are the most frequent causing genes to apparent autosomal recessive non-syndromic hearing loss. Methods In this experimental and case–control study, 17 male Wistar rats were randomly divided into exposure groups (n = 12) and without exposure (n = 5). First group was exposed to noise (90–120 dB, 70 Hz–16 kHz, 8 h/day) for 3–6 days. Cochlear biopsies performed 1 h and 1 week post-exposure, relative gene expression levels were calculated using $${2}^{-\Delta \Delta Ct}$$ 2 - Δ Δ C t . From each group, one ear was stained by hematoxylin and eosin method for histopathological survey. Real-time PCR technique took place, and gene expression data were normalized by GAPDH gene. One-way ANOVA test was performed with a significance level of 0.05 by GraphPad prism software. Results Both GJB2 and SLC26A4 in all groups were down-regulated after exposure compared to their controls. Fold changes in the highest times were related to 1 week after 6 days of exposure, 0.052 and 0.015, respectively. Serious damages occurred in different parts of cochlea, and they were more severe after 6 days and 1-week later. Conclusion It is expected that if the hearing threshold tests be performed before/after exposure and considering longer post-exposure times, subsequently, the expression of these genes does not return to basal level, and irrecoverable damage to the cochlea, progressive and irreversible ARNSHL will be expected.

Background: Noise, a physical factor in most work environments, has many effects on human health. Exposure to excessive noise can modify the expression of associated genes with NIHL. The aim of this study to elucidate changes in expression of GJB2 and SLC26A4 after exposure to intense noise which are the most frequent causing genes to apparent autosomal recessive non-syndromic hearing loss. Methods: In this experimental and case–control study, 17 male Wistar rats were randomly divided into exposure groups (n = 12) and without exposure (n = 5). First group was exposed to noise (90–120 dB, 70 Hz–16 kHz, 8 h/day) for 3–6 days. Cochlear biopsies performed 1 h and 1 week post-exposure, relative gene expression levels were calculated using 2 - Δ Δ C t . From each group, one ear was stained by hematoxylin and eosin method for histopathological survey. Real-time PCR technique took place, and gene expression data were normalized by GAPDH gene. One-way ANOVA test was performed with a significance level of 0.05 by GraphPad prism software. Results: Both GJB2 and SLC26A4 in all groups were down-regulated after exposure compared to their controls. Fold changes in the highest times were related to 1 week after 6 days of exposure, 0.052 and 0.015, respectively. Serious damages occurred in different parts of cochlea, and they were more severe after 6 days and 1-week later. Conclusion: It is expected that if the hearing threshold tests be performed before/after exposure and considering longer post-exposure times, subsequently, the expression of these genes does not return to basal level, and irrecoverable damage to the cochlea, progressive and irreversible ARNSHL will be expected. [ABSTRACT FROM AUTHOR]

Objective: To analyze the hearing phenotypes of p. V37I homozygote and compound heterozygote mutation in GJB2 gene, and to provide basis for genetic counseling. Methods: Fifty-three subjects with p. V37I homozygote and compound heterozygote mutation were recruited at Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital from January 2023 to March 2024. All subjects received universal newborn hearing screening（UNHS）, 23-site chip neonatal deafness genetic screening and audiological tests, including ABR, acoustic immittance, DPOAE, ASSR. The results of newborn hearing screening and hearing diagnosis were compared between homozygous mutation group of 30 cases and compound heterozygous mutation group of 23 cases. Results: In 53 cases, the overall refer rate of UNHS was 64.15%（34/53）, the refer rate of homozygous mutation group was 80.00%（24/30）, which was higher than that of compound heterozygous mutation group（43.48%, 10/23）, the difference between the two groups was statistically significant（ P <0.05）. Three subjects with p. V37I compound heterozygous mutation had passed UNHS and diagnosed with unilateral mild hearing loss. The average age of diagnosis of 53 cases was （3.77±1.40） months, 25 cases with hearing loss accounted for 47.17%, including 13 cases with unilateral, 12 cases with bilateral, 28 cases with normal hearing accounted for 52.83%. There was no significant difference between homozygous mutation group（56.67%, 17/30） and compound heterozygous mutation group（34.78%, 8/23） in the proportion of confirmed hearing loss（ P >0.05）. Among 37 ears of 25 patients with hearing loss, the proportion of mild, moderate and profound hearing loss were 70.27%（26/37）, 27.03%（10/37） and 2.70%（1/37）, respectively. The hearing loss degree of the homozygous mutation group and the compound heterozygous mutation group were mainly mild, accounting for 70.37%（19/27） and 70.00%（7/10） respectively. There was no significant difference between the two groups in the distribution of hearing loss degree（ P >0.05）. Conclusion: The probability of hearing loss was 47.17% in infants of GJB2 gene p. V37I homozygote and compound heterozygote mutation, mainly mild hearing loss. There was no difference in the probability of hearing loss and the distribution of hearing loss degree between the two groups. Patients with p. V37I homozygous and compound heterozygous mutation currently diagnosed as normal hearing need continuous clinical follow-up., 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.)

Dominant variants in the gap junction beta-2 (GJB2) gene may lead to various degrees of syndromic hearing loss (SHL) which is manifest as sensorineural hearing impairment and hyperproliferative epidermal disorders, including palmoplantar keratoderma with deafness (PPKDFN). So far, only a few GJB2 dominant variants causing PPKDFN have been discovered. Through the whole-exome sequencing (WES), a Chinese female patient with severe palmoplantar hyperkeratosis and delayed-onset hearing loss has been identified. She had a novel heterozygous variant, c.224G>C (p.R75P), in the GJB2 gene, which was unreported previously. The proband's mother who had a mild phenotype was suggested the possibility of mosaicism by WES (~120×), and the ultra-deep targeted sequencing (~20,000×) was used for detecting low-level mosaic variants which provided accurate recurrence-risk estimates and genetic counseling. In addition, the analysis of protein structure indicated that the structural stability and permeability of the connexin 26 (Cx26) gap junction channel may be disrupted by the p.R75P variant. Through retrospective analysis, it is detected that the junction of extracellular region-1 (EC1) and transmembrane region-2 (TM2) is a variant hotspot for PPKDFN, such as p.R75. Our report reflects the important and effective diagnostic role of WES in PPKDFN and low-level mosaicism, expands the spectrum of the GJB2 variant, and furthermore provides strong proof about the relevance between the p.R75P variant in GJB2 and PPKDFN. [ABSTRACT FROM AUTHOR]

Objective To analyze the mutations of GJB2，SLC26A4，GJB3，and mitochondrial 12S rRNA genes in 5 562 newborns born from September 2019 to August 2021 in Wuxi City. Methods The heel blood of 5 562 newborns born in Wuxi City from September 2019 to August 2021 was collected. The related genes GJB2，SLC26A4，GJB3，and mi⁃ tochondrial 12S rRNA genes were detected by fluorescence PCR fusion curve and Sanger sequencing. Results There were 336 cases（6. 04%，336/5562）of hearing loss（HL）gene mutations in 5 562 newborns，including 158 cases （2. 84%，158/5562）of GJB2 gene mutations，127 cases（2. 28%，127/5562）of SLC26A4 gene mutations，29 cases （0. 52%，29/5562）of GJB3 gene mutations，18 cases（0. 32%，18/5562）of mitochondrial 12S rRNA gene mutations and 4 cases（0. 07%，4/5562）of compound GJB2 and SLC26A4 gene mutations. Among 5 437 newborns who passed the hearing screening，317 had HL mutations，including GJB2（146 cases），SLC26A4（120 cases），GJB3（29 cas⁃ es），mitochondrial 12S rRNA（18 cases），and complex GJB2 and SLC26A4 genes（4 cases）；among the 125 cases that failed the hearing screening，19 cases had HL mutations，including GJB2 （12 cases） and SLC26A4 （7 cases）. The main mutation sites of GJB2 gene were c. 235delC，c. 299_ 300delAT，and c. 176_ 191del16，etc；the mutation sites of SLC26A4 gene were c. 919-2A>G，c. 2168A>G，and c. 1226G>A；the mutation sites of GJB3 gene included c. 538C>T and c. 547G > A；mitochondrial 12S rRNA gene mutations were m. 1555A>G homogeneous mutation，m. 1503G>A homo⁃ geneous mutation，and m. 1555A>G heterogeneous mutation，etc. The mutation rates of newborns who failed the hearing screening were higher；their types of mutations with higher mutation rates were c. 235delC homozygous mutation of GJB2 gene and c. 1226G>A homozygous mutation of SLC26A4 gene，followed by c. 2168A>G heterozygous mutation of SLC26A4 gene. Conclusions GJB2 gene mutation is the most common cause of neonatal hearing loss in Wuxi City，followed by the SLC26A4 gene，GJB3 gene，and mitochondrial 12S rRNA gene；the mutation type of hearing loss is mainly heterozy⁃ gous mutation；the hearing loss gene loci with the highest mutation frequency are GJB2 gene c. 235delC，SLC26A4 gene c. 919-2A>G and GJB2 gene c. 299_300delAT locus. The common hearing loss gene mutations in newborns who fail the hearing screening are c. 235delC homozygous mutation of GJB2 gene，c. 1226G>A homozygous mutation of SLC26A4 gene，and c. 2168>G heterozygous mutation. [ABSTRACT FROM AUTHOR]

Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital ectodermal dysplastic syndrome presenting with keratitis, ichthyosis and sensorineural hearing loss. The most common causes of KID syndrome are heterozygous missense mutations in the GJB2 gene that codes for connexin 26. During the ophthalmological examination, two adult females complained of recent worsening of visual acuity in both eyes. Anamnesis revealed that their eyes were red and irritated from early childhood onwards. Both of them had thickening and keratinisation of eyelid margins, lash loss, diffuse opacification of cornea and conjunctiva caused by keratinisation of eye surface, superficial and deep corneal vascularisation and corneal oedema. Partial sensorineural hearing loss and difficulties in speech were also noted along with typical ichthyosiform erythroderma. Genetic testing of the GJB2 gene revealed a heterozygous p.D50N mutation in both patients. Patients were treated with a combined topical corticosteroid and artificial tears therapy, with steroid therapy being intensified during the last month. The therapy increased the visual acuity by decreasing corneal oedema and by forming a more regular air-tear interface during the six months follow up. Subsequently, the disease progressed despite the continuation of the therapy. This is the first report of Serbian patients with KID syndrome. Despite the administration of the combined topical corticosteroid and artificial tears therapy the disease is relentlessly progressive and therapeutic success of ophthalmological signs with local therapeutic modalities used so far had been disappointing. [ABSTRACT FROM AUTHOR]

Objective: Hearing loss (HL) is one of the most prevalent chronic conditions in children and has consequences in speech, language, education, and social functioning which impede the quality of life. Due to the major involvement of the genetic factors in HL, especially non-syndromic HL (NSHL), genetic diagnosis and genetic counseling have a major impact on early management of the affected individuals and their families. Herein, we report the GJB2 gene variants and their frequencies in NSHL cohort at a tertiary health center between 2002-2021 to contribute for the future genetic counseling of Turkish NSHL patients. Materials and Methods: Two exons of the GJB2 gene were amplified in 402 NSHL patients by two separate PCR reactions and sequenced using the Sanger technique. Results: We found 13 different GJB2 variants in 35% (141/402) of the patients with NSHL. 53.9% were homozygous and 33.3% were compound heterozygous for the most common (59.21%) variant, c.35delG. Approximately 13% of the patients were found to carry the variants in the heterozygous state. The most frequent GJB2 variant c.35delG was followed by c.71G>A (6.38%), c.-23+1G>A (3.54%) and c.233delG (2.48%). We found heterozygous p.Asp50Glu (c.150C>A) alteration in four of eight patients with keratitis, ichthyosis, deafness (KID) and palmoplantar keratoderma (PPK) syndrome. Conclusion: Our results further emphasize the well-known prevalance of the GJB2 c.35delG alteration being the most predominant variant in the Turkish NSHL patients. The high rate of mono-allelic state could be considered as coincidental due to high allelic heterogeneity of NSHL, or possibly suggestive for digenic inheritance. [ABSTRACT FROM AUTHOR]

Background and Aim: Non-syndromic hearing loss is a genetically heterogeneous disorder. Mutation in the GJB2 gene is a major cause of non-syndromic hearing loss in numerous countries. This study aimed to evaluate GJB2 mutations in 31 individuals with non-syndromic hearing loss Methods & Materials: In this descriptive cross-sectional study, the required blood samples were collected from 31 individuals with non-syndromic hearing loss in Rasht and Bandar Anzali Cities, Gilan Province, Iran. After DNA isolation, the GJB2 gene was amplified by the PCR method and underwent sequencing. Ethical Considerations:This study was approved by the Ethics Committee of the Islamic Azad University, Mashhad Branch (Code: IR.IAU.MSHD.REC.1398.027). Results: In this study, 3 mutations were determined in 18 individuals with hearing loss. Accordingly, 35delG mutation had the highest frequency (48.38%) in individuals with hearing loss as homozygote (n=14) and heterozygote (n=2). A patient with heterozygosity in V153I mutation and a patient with compound heterozygosity in 35delG/G200R mutation was determined. Conclusion: It appears that 35delG mutation is a common mutation in the GJB2 gene in individuals with non-syndromic hearing loss in Guilan Province.

Introduction/Objective. Hearing impairment is the most common sensorineural disorder with an incidence of 1/700–1000 newborns. Variants in the GJB2 gene are the major cause of autosomal recessive nonsyndromic sensorineural hearing loss (ARNSHL). The degree of hearing impairment in patients with detected mutations in GJB2 gene ranges from mild to profound. The aim of this study was to determine possible genotype–phenotype association between audiometric characteristics and detected genotypes in ARNSHL patients from Serbia. Methods. Ninety-two patients with ARNSHL underwent genetic analysis with amplification-refractory mutation system polymerase chain reaction and sequencing of the GJB2 gene. Audiological analyses were obtained in all patients using a combination of several methods to estimate the degree of hearing loss. Results. Audiological analysis performed in the 92 probands showed moderate to profound range of hearing loss. All identified pathogenic variants accounted for 42.39% of the mutant alleles (78/184 alleles), with the c.35delG mutation being the most frequent one (30.43%). Genotype–phenotype correlation in an isolated group of 37 patients bearing c.35delG in the homozygous, compound heterozygous, or heterozygous state. In this group the majority of patients (30/37, 81.08%) exhibited severe to profound hearing deficit. Conclusion. Association between genotype and the degree of hearing impairment in patients analyzed in this study demonstrated that patients with bi-allelic truncating mutations, i.e., c.35delG, associate with the more severe hearing loss when compared with those identified with only one affected allele. The various degrees of hearing impairment observed in heterozygous patients could be explained by the presence of an undetected second mutation or other modifier genes or environmental causes.

Interstitial 2q24.2q24.3 microdeletions are rare cytogenetic aberrations associated with heterogeneous clinical features depending on the size of the deletion. Here, we describe 2 patients with overlapping de novo 2q24.2q24.3 deletions, characterized by array-CGH. This is the smallest 2q24.2q24.3 region of overlap described in the literature encompassing only 9 genes (SLC4A10, DPP4, GCG, FAP, IFIH1, GCA, KCNH7, FIGN, GRB14). We focused our attention on SLC4A10, DPP4, and KCNH7, genes associated with neurological features. Our patients presented similar features: intellectual disability, developmental and language delay, hypotonia, joint laxity, and dysmorphic features. Only patient 2 showed profound deafness and also carried a heterozygous mutation of the GJB2 gene responsible for autosomal recessive deafness 1A (DFNB1A: OMIM 220290). Could the disruption of a gene present in the 2q24.2q24.3 deleted region be responsible for her profound hearing loss? [ABSTRACT FROM AUTHOR]

Hearing impairment is the most common sensorineural disorder in humans and many genes have been identified as causable. Despite genetic heterogeneity, a single locus, DFNB1, that contains genes GJB2 and GJB6, accounts for up to 50% of all cases. Aim of this study was to determine prevalence of identified variants in DFNB1 locus in patients from Serbia with autosomal recessive non-syndromic hearing loss (ARNSHL). In this study, PCR-ARMS and direct sequencing of the GJB2 and GJB6 genes was carried out in 54 probands and relatives from Serbia with nonsyndromic hearing loss (NSHL). In 31 patients a series of variants have been identified in the GJB2 gene. Fully characterized genotype with bi-allelic mutations was observed in 40.74% of the probands (22/54). The remaining probands were either identified in the heterozygote form (9/54) or were identified with no (23/54) causing variants for the tested genes. A total of seven different mutations were found with following allele frequencies: c.35delG (31.48%), c.71G>A (6.48%), c.313_326del (5.56%), c.101T>C (1.85%), c.380G>A (1.85%), c.79G>A (0.92%) and c.269T>C (0.92%). The molecular basis of NSHL in patients from Serbia was analyzed for the first time in this study. The results have important implication to the development of the genetic diagnosis of deafness, genetic counseling, and early treatment in our country. Also, our findings contribute to the knowledge of geographic distribution of DFNB1 mutations. [ABSTRACT FROM AUTHOR]

The development of next generation sequencing techniques has facilitated the detection of mutations at an unprecedented rate. These efficient tools have been particularly beneficial for extremely heterogeneous disorders such as autosomal recessive non-syndromic hearing loss, the most common form of genetic deafness. GJB2 mutations are the most common cause of hereditary hearing loss. Amongst them the NM_004004.5: c.506G > A (p.Cys169Tyr) mutation has been associated with varying severity of hearing loss with unclear segregation patterns. In this study, we report a large consanguineous Emirati family with severe to profound hearing loss fully segregating the GJB2 missense mutation p.Cys169Tyr. Whole exome sequencing (WES), in silico, splicing and expression analyses ruled out the implication of any other variants and confirmed the implication of the p.Cys169Tyr mutation in this deafness family. We also show preliminary murine expression analysis that suggests a link between the TMEM59 gene and the hearing process. The present study improves our understanding of the molecular pathogenesis of hearing loss. It also emphasizes the significance of combining next generation sequencing approaches and segregation analyses especially in the diagnosis of disorders characterized by complex genetic heterogeneity. [ABSTRACT FROM AUTHOR]

Abstract Autosomal recessive nonsyndromic hearing loss (ARNSHL) is a genetically heterogeneous neurosensory disorder, usually characterized by congenital or prelingual hearing loss. We report a Han Chinese male, born to consanguineous parents, presenting with nonsyndromic sensorineural hearing loss, whose clinical phenotype was also consistent with auditory neuropathy spectrum disorder (ANSD). After exome sequencing, a gap junction protein beta 2 gene (GJB2) c.235delC variant in the homozygous state was detected in the patient. Both parents were heterozygous for this variant, as documented by Sanger sequencing. The known pathogenic GJB2 c.235delC variant was not detected in 200 healthy controls. It is predicted to be a disease-causing alteration by generating a truncated protein p.(L79Cfs*3), disturbing the appropriate folding and/or oligomerization of connexins and leading to defective gap junction channels. This study shows that the association of homozygosity of the GJB2 c.235delC variant with ARNSHL and ANSD in a patient.

Background and Aim Non-syndromic hearing loss is a genetically heterogeneous disorder. Mutation in the GJB2 gene is a major cause of non-syndromic hearing loss in numerous countries. This study aimed to evaluate GJB2 mutations in 31 individuals with non-syndromic hearing loss Methods & Materials In this descriptive cross-sectional study, the required blood samples were collected from 31 individuals with non-syndromic hearing loss in Rasht and Bandar Anzali Cities, Gilan Province, Iran. After DNA isolation, the GJB2 gene was amplified by the PCR method and underwent sequencing. Ethical Considerations This study was approved by the Ethics Committee of the Islamic Azad University, Mashhad Branch (Code: IR.IAU.MSHD.REC.1398.027). Results In this study, 3 mutations were determined in 18 individuals with hearing loss. Accordingly, 35delG mutation had the highest frequency (48.38%) in individuals with hearing loss as homozygote (n=14) and heterozygote (n=2). A patient with heterozygosity in V153I mutation and a patient with compound heterozygosity in 35delG/G200R mutation was determined. Conclusion It appears that 35delG mutation is a common mutation in the GJB2 gene in individuals with non-syndromic hearing loss in Guilan Province. [ABSTRACT FROM AUTHOR]

Congenital deafness is one of the common disorders, with some common genes accounting for most of the cases. One in 1000 children are born with sensorineural hearing loss, and of that 50% are hereditary. In the Mediterranean Europeans, 80% of the nonsyndromic recessive deafness is due to homozygous mutation in GJB2, the 35del G allele. In Western population, the GJB2 variation have been found in up to 30–40% cases. In Indians, the GJB2 variants have been found in up to 20% cases, mostly from central and southern India. In the present study, DNA was extracted from blood using standard methods. This was used to perform targeted gene capture using a custom capture kit. Multiple genes causing deafness were sequenced by next-generation sequencing to mean [ 80–100x coverage on Illumina sequencing platform. We found variants in GJB2, WFS1, FGF3, EYA4, MYO7A and CHD7 genes. Most of these variants were pathogenic and novel, and possibly causative. Deafness is most commonly due to the autosomal dominant genes but in severe cases of early onset deafness, autosomal recessive genes may contribute in our population. In selected families of severe prelingual deafness, prenatal diagnosis can be done. [ABSTRACT FROM AUTHOR]

Reduction of hearing is the most common sensory impairment among newborns with an incidence of 1-3 per 1000 births. Introduction of an Auditory Newborn screening program allows early identification of hearing impairment. Mainly, congenital hearing loss in early childhood is a result of genetic changes. Due to high frequency of GJB2 pathogenic variants, its molecular characterization among sensorineural hearing reduction cases is already conducted as a routine analysis in many countries. The aim of this study is to show our initial results in the effort to determine whether genetic screening along with the standard hearing screening in newborns is justified. Otoacoustic emission (OAE) method was conducted in 223 newborns at risk of hearing impairment. Among them, 7 did not pass the test in both ears while 9 exhibited one-sided hearing loss. In all 7 children with indication of profound bilateral deafness, the diagnosis was confirmed using auditory brainstem response. Genetic screening of GJB2 gene was performed in 6 of them. Genetic analysis of GJB2 revealed homozygous state of the most common pathogenic variant 35delG in 3 (50%) of the analyzed infants. In the remaining 3 no pathogenic variant was determined. The results indicate that performing auditory OAE together with genetic screening is justified. In newborns who have not passed the hearing screening test and have profound hearing loss, without other syndrome traits, screening for mutations of GJB2 gene should be conducted. Genetic screening enables establishment of early definite diagnosis for deafness and helps in conducting adequate therapy providing timely rehabilitation and social inclusion of deaf child. [ABSTRACT FROM AUTHOR]

Background Consanguineous marriage, a common practice in South India, increase the incidence of autosomal recessive diseases such as nonsyndromic hearing loss (NSHL) in offspring. This trend was noted in the children with hearing impairment (HI) who received cochlear implants (CI) at our University hospital in Porur, Chennai, India. To ascertain the genetic etiology of HI in these patients, we performed multiplex ligation-dependent probe amplification (MLPA) analysis. Methods A total of 25 families who had a child with NSHL were included in the study. MLPA screening of GJB2 , GJB6 , and GJB3 was performed for all the recruited individuals. Results The pathogenic p.W24X* mutation of GJB2 was detected in 2 patients; both of their parents were heterozygous carriers. Both families had a second-degree consanguineous marriage. Conclusion This study has important implications for molecular-diagnosis strategy and genetic counseling for families with HI in South India. [ABSTRACT FROM AUTHOR]

Background: Sensorineural hearing loss (SNHL) is a clinically and genetically heterogeneous disease. In some populations, c.365delG mutation in the GJB2 gene represents the most frequent cause of hereditary SNHL. The great diversity of mutations in the GJB2 gene worldwide highlights the participation of ethnic background in SNHL. Objective: To describe the presence of homozygous c.del35G mutation in the GJB2 gene in a Mexican family with SNHL. Materials and methods: A Mexican family with SNHL was included in the study. Analysis of the GJB2 gene was performed through whole exome sequencing (WES) and DNA direct sequencing analysis in all members of the family and in 100 normal controls Results: Affected sibs showed the homozygous c.del35G mutation in the GJB2 gene. Parents of the families were heterozygous for the molecular defect and had normal audition. Conclusion: We describe a homozygous c.del35G mutation in the GJB2 gene through WES analysis, a homozygous mutation with a very low occurrence in Mexican population.

Genetic contributing factors to non-syndromic hearing loss (NSHL) are remarkably diverse spanning over autosomal to X-linked to mitochondrial inheritance patterns. Facing a quite unconventional pedigree, here we report implementation of whole exome sequencing (WES) to uncover mitochondrial pathogenic variant in a six-generation Iranian family with four cases affected with hereditary NSHL of variable severity. As a result, heteroplasmic transition of A to G at position 1555 of MT-RNR1 gene was identified in all affected individuals co-existing with nuclear c.28G > T (p.A10S) variant in the TRMU gene, only in some patients. The reliability of WES to infer nuclear as well as mitochondrial variants in hearing loss were discussed. • It was only in 2015 which applicability of off-target reads from exome sequencing to extract mitochondrial single nucleotide variants and heteroplasmy was confirmed (Pan Zhang et al., Brief Bioinform.). • Since then, WES has been applied to detect mitochondrial mutations in a few genetic disorders but not in hearing loss, yet. • As the most common birth defect in almost all populations, hearing impairment could result from both, nuclear and mitochondrial mutations and could appear in almost all the patterns of inheritance. Therefore, identification of causative mutation can be extremely challenging. • In this manuscript we studied genetic cause of the non-syndromic hearing loss in a six-generation Iranian family with multiple affected individuals. • Due to the various disease severities, the certain pattern of inheritance could not be identified, solely based on the pedigree. Therefore, whole exome sequencing was performed. • Through filtration of numerous variations, we successfully captured A1555G variation in MT-RNR1 gene, which had been reported as a rare cause of non-syndromic hearing loss (NSHL). • The mutation was then confirmed with PCR-RFLP, a common method to identify the above-mentioned variation. • In fact here we report, for the first time, that whole exome sequencing could reliably be used for the detection of mitochondrial variants to identify the genetic cause of hearing impairment. • This study provides another evidence for the application of whole exome sequencing in clinical genetics once the nuclear and mitochondrial variations might equally be involved. [ABSTRACT FROM AUTHOR]

Previous studies have linked GJB2 gene and mitochondrial DNA (mtDNA) mutations to nonsyndromic hearing impairment (NSHI), but no study in China has yet investigated these mutations across all age groups. To fill the gap, this study ascertained 263 patients with NSHI between ages 2 months and 60 years and analyzed the presence of GJB2 gene and mtDNA A1555G/C1494T mutations by polymerase chain reaction (PCR) and DNA sequencing. A total of 20 types of mutations were detected for the GJB2 gene. The GJB2 gene and mtDNA A1555G/C1494T mutations were detected in 18.63 and 11.41% cases, respectively. At the first hospital visit, GJB2 gene mutations were detected in 5.97% of adult patients (>18 years) and 22.96% pediatric patients (

Key Clinical Message: Here, we report a novel deletion (copy number variation: CNV) in the GJB2 gene observed in a Japanese hearing loss patient. The deleted segment started in the middle of the GJB2 gene, but the GJB6 gene remained intact. This partial deletion in the GJB2 gene highlights the need for further improvements in GJB2 screening. Here, we report a novel deletion in the GJB2 gene observed in a Japanese hearing loss patient. The deleted segment started in the middle of the GJB2 gene, but the GJB6 gene remained intact. This partial deletion in the GJB2 gene highlights the need for further improvements in GJB2 screening. [ABSTRACT FROM AUTHOR]

Autosomal recessive (AR) non-syndromic hearing loss (NSHL) is the most common form of hereditary deafness. Mutations in the gap junction protein beta 2 (GJB2) gene encoding connexin 26 (Cx26) account for about 50% of cases of ARNSHL. In the current study, a combination of exome sequencing and Sanger sequencing in a Chinese Dong family with ARNSHL allowed identification of a novel compound heterozygous mutation c.240G>C(p. Q80H)/C.109G>A(p.V37I) in exon 2 of the GJB2 gene, which co-segregated with the disease phenotype in this family and was not evident in 100 healthy controls. Bioinformatic analysis revealed that the two mutations in the GJB2 gene were probably pathogenic. Results indicated that the compound heterozygous variants, p.Q80H and p.V37I, in the GJB2 gene are associated with ARNSHL. The Q80H variant was initially identified in patients of Dong Chinese origin with NSHL. The current results broaden the spectrum of GJB2 mutations responsible for NSHL and have important implications for molecular diagnosis, treatment, and genetic counseling for this family. [ABSTRACT FROM AUTHOR]

The current study retrospectively investigated variations in audiological phenotypes in children with GJB2 gene mutations. Subjects were 128 infants and young children who were seen as outpatients by Otology at Beijing Tongren Hospital from 2012 to 2018. Of the 128 subjects, 99 had biallelic truncating (T/T) mutations and 29 had truncating/nontruncating (T/NT) mutations. Genotypes, results of universal newborn hearing screening (UNHS), and the degree and symmetry of hearing loss were examined in the two groups. Twenty-two subjects (20.37%, 22/128) passed UNHS, including 13 children with T/T mutations and 9 with T/NT mutations. Of the 128 subjects, 22 had normal hearing, 2 had unilateral hearing loss, and 115 had bilateral hearing loss. Severe-to-profound hearing loss was the most prevalent phenotype in children with T/T mutations (73.23%), while normal hearing was prevalent in children with T/NT mutations (41.38%). Symmetrical hearing loss was the main phenotype in both groups, and the number of subjects with symmetrical hearing loss did not differ significantly between the two groups. Therefore, children with GJB2 gene mutations have phenotypic variability in terms of their results of UNHS and their degree and symmetry of hearing loss. Subjects with T/NT mutations of the GJB2 gene were more likely to pass UNHS and had milder hearing loss compared to those with T/T mutations. Symmetrical hearing loss was the main phenotype in the two groups, but 36.53% of children had bilateral asymmetric hearing loss. Parents of all subjects with sensorineural hearing loss were informed that their children may have a GJB2 mutation. [ABSTRACT FROM AUTHOR]

Autosomal recessive deafness type 1A (DFNB1A) caused by mutations in the GJB2 gene (Cx26) is the main cause of nonsyndromic hearing impairment in many populations worldwide. It is considered that widespread prevalence of DFNB1A can be due to the long tradition of intermarriages between deaf people (assortative marriages) combined with their increased social adaptation and genetic fitness after widespread introduction of sign language. For the first time, the data on mating structure and reproduction of deaf people living in Yakutia (Eastern Siberia, Russia) are presented in comparison with contribution of the GJB2 gene mutations to the etiology of hearing impairment. The relative fertility of deaf people compared to their hearing siblings is 0.78 (mean number of children 1.76 ± 0.10 and 2.24 ± 0.09 to deaf and their hearing siblings, respectively, p = 0.0018). The rate of assortative marriages among deaf people is 77.1% (81 of 105 marriages). Biallelic mutations in the GJB2 gene were found in 42.2% (43 of 102) of examined deaf people, which corresponded to diagnosis DFNB1A for these patients. A comparison of deaf marital partners by GJB2 status revealed a proportion of noncomplementary marriages (24%) in which hearing loss in both partners was caused by the presence of biallelic GJB2 gene mutations resulting in the birth of only deaf children in such couples. Thus, the set of obtained data including a relatively high genetic fitness (expressed as relative fertility) of deaf people in Yakutia in combination with a high rate of assortative marriages among them and high incidence of DFNB1A indicates a possible weakening of selection against such trait as “deafness” and a possible increase in the frequency of GJB2 mutant alleles in subsequent generations. [ABSTRACT FROM AUTHOR]

Hereditary hearing impairment (HI) caused by recessive GJB2 mutations is a frequent sensory disorder. The results of the molecular-based studies of HI are widely used in various genetic test systems. However, the ethical aspects are less described than the genetic aspects. The concerns expressed by individuals from groups with genetic risks must be included in the counseling of patients and their families. For evaluation of subjective opinions of hearing parents about the presumed causes of HI of their children, we analyze the cohort of parents having children with confirmed hereditary HI caused by biallelic recessive GJB2 mutations (in a homozygous or a compound heterozygous state). This study included 70 deaf children with HI due to mutations in the GJB2 gene and 91 questionnaires about the presumed causes of their deafness filled by their parents. Most of the parents at 78% (CI 68.4-85.4%) attributed their children's HI to 'non-hereditary' causes and 22% (CI 14.7-31.6%) to 'hereditary' causes ( p < 0.05). Therefore, the prior opinions of the parents did not correspond to positive GJB2 genetic testing results. The subjective opinions of parents are probably partly based on family history, since respondents with deaf relatives in their pedigree more likely supposed hereditary causes for HI in their children than the respondents without deaf relatives ( p < 0.001). [ABSTRACT FROM AUTHOR]

OBJECTIVE: Gene chip and gene sequencing techniques were used to detect the main pathogenic genes in pregnant women with hereditary hearing loss. PATIENTS AND METHODS: From May 2015 to May 2016, 1080 pregnant in Xuzhou Maternal and Child Health Hospital were enrolled in this study. Women age range was 18 to 40 years. 4 genes and 9 mutation sites, including 4 sites (35delG, 176, 235delC and 299) in GJB2 gene, 2 sites (2168A>G and IVS-7-2A>G) in SLC26A4 (PDS) gene, 2 sites (1494C>T and 1555A>G) in 12s rRNA gene and 1 site (538C>T) in GJB3 gene, were detected using the GeeDom® 9-item hereditary hearing loss gene detection kit. Deafness genes in the husband of the pregnant woman with GJB2 and SLC26A4 positive gene mutations were verified using Sanger sequencing. Fetuses with the same deafness genes as their parents were diagnosed before delivery using amniocentesis. RESULTS: 48 patients (4.45 %) were detected positive for hereditary hearing loss. Most of them (28 cases) were identified with GJB2 gene mutation (1 case with 176 site mutation, 22 cases with 235delC site mutation and 5 cases with 299 site mutation). We had 15 cases of the SLC26A4 gene mutation (3 cases of 2168A>G site mutation and 12 cases of IVS-7-2A>G site mutation), 2 cases of 538C>T site mutation of GJB3 gene and 3 cases of 1555A>G site mutation of 12s rRNA gene. CONCLUSIONS: The gene detection technique has a great health-economic significance in screening the main pathogenic genes involved in the hereditary hearing loss. [ABSTRACT FROM AUTHOR]

GJB2 gene encodes connexin 26 which is an important skin-expressed gap junction protein. Connexin 26 is a transmembrane protein that is involved in the potassium ion recycling pathway in the inner ear. In this study, the neutrality tests were performed on genotyping data obtained from three polymorphic markers SNP1245, D13S141 and D13S175, located within the GJB2 region. The population genetics analysis packages, PyPop and Popgene32, were used for the analysis of the data obtained from Iranian population. Fnd value of three markers, SNP1245, D13S141 and D13S175, in Iranian population was estimated -0.5980, -1.0155 and -0.6457, respectivelybut without significant P values. The results indicated the influence of balancing selection on polymorphic markers at GJB2 gene. In the studied population, the F value of three markers lied inside L95 and U95 region of expected F value which showed no effect of genetic hitchhiking on markers located within GJB2 region. The results obtained from this study indicated that the polymorphism of these three markers in GJB2 gene was maintained by higher adaptive value of heterozygotes in Iranian population.