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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.

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.

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]

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]

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]

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.

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]

Mutations in the GJB2 gene, encoding connexin 26 (Cx26), are a major cause of nonsyndromic recessive hearing loss in many countries. We report here on a novel point mutation in GJB2, p.L76P (c.227C>T), in compound heterozygosity with a c.35delG mutation, in two Brazilian sibs, one presenting mild and the other profound nonsyndromic neurosensorial hearing impairment. Their father, who carried a wild-type allele and a p.L76P mutation, had normal hearing. The mutation leads to the substitution of leucine (L) by proline (P) at residue 76, an evolutionarily conserved position in Cx26 as well as in other connexins. This mutation is predicted to affect the first extracellular domain (EC1) or the second transmembrane domain (TM2). EC1 is important for connexon-connexon interaction and for the control of channel voltage gating. The segregation of the c.227C>T (p.L76P) mutation together with c.35delG in this family indicates a recessive mode of inheritance. The association between the p.L76P mutation and hearing impairment is further supported by its absence in a normal hearing control group of 100 individuals, 50 European-Brazilians and 50 African-Brazilians.

"nBackground: Mutations of GJB2 gene encoding connexion 26 are the most common cause of hearing loss in many popula­tions. A very wide spectrum of GJB2 gene mutations associated with hearing loss have been detected but pathogenic role has been tested only for a part of them. In this study, we have provided genetic evidence on the pathogenicity of our previ­ously reported novel GJB2 allelic variants. "nMethods: The pathogenic role of GJB2 allelic variants were assessed using co segregation of each allelic variant with hear­ing loss in family members, absence of the allelic variants in control populations, coexistence with a second GJB2 mutation, na­ture of the amino acid substitution and evolutionary conservation of the appropriate amino acid. "nResults: The GJB2 allelic variants including 363delC, 327delGGinsA, H16R and G200R have been co segregated with auto­somal recessive non syndromic hearing loss in five families and are not found in control subjects. The G130V and K102Q were found in heterozygous state in two deaf individuals. G130V results in an exchange a residue highly conserved among all the connexins but was found with a rate of 1% in control subjects and K102Q results in an exchange a residue not con­served among all the connexins and not identified in control subjects. "nConclusion: We conclude that, 363delC, 327delGGinsA, H16R and G200R may be pathogenic. However, the pathogenic­ity and inheritance of K102Q and G130V can not be assessed clearly and remains to be identified.

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-Ca 2+ 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-Ca 2+ signals. Clarifying the pathological mechanism of GJB2 -related hearing loss can help develop new prevention and treatment strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Jin, Zhang, Xiong, Gu, Zeng and Chen.)

Conclusion: This study demonstrates that the gap junction protein beta-2 gene (GJB2) p.R32C and p.L79Cfs*3 variants are associated to a consanguineous family with autosomal recessive non-syndromic hearing loss (ARNSHL). The p.R32C variant is found for the first time in the NSHL patients of Han Chinese origin. The finding sheds new light on the accurate genetic diagnosis and counseling for the family.Objective: ARNSHL is a highly heterogeneous genetic disease. ARNSHL usually displays non-progressive congenital or pre-lingual deafness. In this study, the aim is to detect the disease-causing mutation(s) in a Han family with ARNSHL.Methods: A consanguineous Han family with ARNSHL was enrolled. Two hundred ethnicity-matched unrelated subjects without any hearing impairments were used as normal controls. Exome sequencing and Sanger sequencing were applied to identify the causative mutation in the ARNSHL family.Results: Compound heterozygous variants c.94C > T (p.R32C) and c.235delC (p.L79Cfs*3) in theGJB2gene were identified in the two patients of the ARNSHL family, and the heterozygousGJB2c.94C > T and c.235delC variants were identified in his unaffected father and mother, respectively. The two variants in theGJB2gene were absent in the 200 unrelated controls. [ABSTRACT FROM PUBLISHER]

Mutations in the GJB2 gene are the most common known cause of hereditary congenital hearing loss. Rapid genomic DNA extraction (RGDE) method was used for genomic DNA extraction. After amplification of coding region of CX26 gene with specific primers, expected PCR products with 724bp length were subjected to direct sequencing in both directions. We describe here a novel heterozygous -T to -C transition at codon 202 (TGC→CGC) of the GJB2 gene in a patient, 40-year-old Iranian woman, which replaces a cysteine with an arginine residue (C202R). The dominant mutation C202R associated with non-syndromic sensorineural hearing loss. This mutation has not previously been described in affected or control samples from other populations investigated for GJB2 mutations, indicating that it is a rare substitution. This dominant mutation was recorded in NCBI GenBank with accession number KF 638275.

Objective To estimate the prevalence of 35delG and Met34Thr variants in a Portuguese children's community sample and to compare these frequencies with nonsyndromic hearing-loss patients. Methods 502 children were randomly selected among the 8647 participants of the Portuguese birth cohort Generation XXI, and screened for Met34Thr and 35delG variants in the GJB2 gene. These variants were also studied on 89 index-cases, observed in the Clinic of “Hereditary Hearing-loss” in Saint John's Hospital Center, presenting a mild to profound nonsyndromic hearing-loss. Results Among the 502 children from Generation XXI, 10 were heterozygous for the 35delG variant (95% Confidence Interval 1.03–3.68) and 1 homozygous (95% Confidence Interval 0.01–1.24). Other 10 children presented heterozygosity for the Met34Thr variant (95% Confidence Interval 1.03–3.68). No homozygous for the Met34Thr or compound heterozygotes (35delG/Met34Thr) were found. In the total of 89 nonsyndromic hearing-loss patients, 5 (95% Confidence Interval 2.11–12.8) were heterozygous and 7 (95% Confidence Interval 3.61–15.6) were homozygous for the 35delG variant. The Met34Thr variant was found in 4 patients, 2 heterozygous (95% Confidence Interval 0.13–8.31) and 2 homozygous (95% Confidence Interval 0.13–8.31). Conclusion The carrier frequency of 35delG and Met34Thr variants in a Portuguese sample was 1 in 50. Our data suggests that the 35delG mutation has an association with deafness. For the Met34Thr variant, no association was observed. However, Met34Thr seemed to conform to an additive model in hearing-loss. [ABSTRACT FROM AUTHOR]

Background Sensorineural hearing loss (SNHL) is a genetically heterogeneous disease. GJB2 gene mutations seem to be the most frequent cause of hereditary hearing impairment in several populations. There is variability in the mutations in the GJB2 gene worldwide; this remarks the influence of ethnic background in SNHL. Objective To describe the presence of two trimutations in the GJB2 gene in two Mexican families with hereditary SNHL. Materials and methods Two unrelated Mexican families with prelingual SNHL were included in the study. Analysis of the GJB2 gene through PCR and DNA direct sequencing analysis was performed in all members of the families and in 100 normal controls. Results Affected member of the family 1 showed the trimutation p.S19R/p.R32S/p.E47*, whereas affected members of the family 2 showed the trimutation p.F31I/p.W44*/p.V84M. Parents of both families were heterozygous with normal audition. Conclusion We found a novel mutation in the GJB2 gene and two trimutations with SNHL not previously reported. This remarks the complexity in the pattern of mutations in the GJB2 gene in SNHL and enriches the spectrum of the type of molecular defects in the GJB2 gene. [ABSTRACT FROM AUTHOR]

Objective To identify the spectrum of mutations in connexin 26 gene and frequency of two deletions in connexin 30 gene in central Iran. Methods After extraction of DNA from 300 blood samples, connexin 26 gene coding region was amplified using specific primers. PCR products were used for bidirectional sequencing. Multiplex PCR was used for detection of del( GJB6 -D13S1830) and del( GJB6 -D13S1854) in the GJB6 gene. Results Eighteen different mutations including two novel variants in GJB2 gene were detected. The GJB2 mutations were observed in 23.3% of all the subjects. In addition, none of the deaf patients carried the del( GJB6 -D13S1830) and del( GJB6 -D13S1854) in the GJB6 gene. The 35delG mutation was the most common mutation, accounting for 32.65% of the mutant alleles. Conclusion The present study indicates that mutations in the GJB2 gene particularly 35delG are important causes for ARNSHL. 60% of the patients were heterozygous carriers. Thus, further investigation is needed to detect the genetic cause of hearing loss in patients with mono allelic mutations in the coding region of GJB2 . [ABSTRACT FROM AUTHOR]

Background Disease-associated mutations in GJB2 gene are one of the major reasons that can cause non-syndromic sensorineural hearing loss (NSHL). GJB2 gene deafness has various clinical phenotypes. This study aims to analyze characteristics and relationships of clinical phenotypes through analyzing 1481 NSHL cases and 190 GJB2 deafness patients (with dual gene mutations). Patients and methods All the patients diagnosed as deaf disease molecular diagnostics were obtained from the people's liberation army general hospital from March 2007 to March 2011. The accession number of GJB2 was NM_004004 in GenBank, and sequence alignment and annotation were performed using GeneTool software. Results In NSHL patients, mutated allele frequency in GJB2 was 20.57%, and the preponderant type was c.235delC (11.84%) followed by c.109G>A (3.75%). Mutation rate of double allelic gene was 16.18%, including 8.43% of homozygous mutation rate and 7.75% of recombination heterozygosis mutation. Moreover, auditory threshold of GJB2 biallelic marker was associated with ages of onset, while no significant correlation was detected with disease time and whether the inner ear malformation. Similar clinical phenotype could be detected between patients with c.109G>A dual gene mutation and dual gene mutation. However, in the aspect of hearing impairment, the phenomenon of pathopoiesia caused by mutation of c.109G>A was poorer than the other mutations, and even near those patients without pathogenic mutations. Conclusion Our study further shows the definite relationship of clinical phenotype and genotype in GJB2 gene correlated deafness, and these results can provide basis for revealing pathogenesis, gene diagnosis and consult of deafness. The level of evidence in the study is level 4 (case series). [ABSTRACT FROM AUTHOR]

Objectives: Mutations in the GJB2 gene have been of particular interest as it is the most common causative gene for congenital deafness in all populations. Detailed audiological features, including genotype-phenotype correlations, have been well documented. However, in spite of abundant gene as well as protein expression in the vestibular end organs, neither vestibular symptoms nor vestibular functions have yet been elucidated. In the present study, vestibular functions were evaluated in patients diagnosed with GJB2-related deafness. Subjects and Methods: Vestibular functions were evaluated by caloric test and cervical vestibular evoked myogenic potential (cVEMP) testing in 24 patients with biallelic GJB2 mutations. Results and Discussion: Twenty-one of 23 patients (91.3%) had normal caloric responses and significantly lower cVEMP amplitudes than the control subjects. In the patients who were able to undergo vestibular testing, the mostly normal reactions to caloric testing indicated that the lateral semicircular canal was intact. However, the majority of GJB2 patients showed low cVEMP reactions, indicating a saccular defect. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

This article reviews the most prevalent sensory illness of mammals especially humans-Genetic Deafness or hearing loss (HL). For genetic hearing loss more than 100 candidate genes have been discovered. The most common candidate gene of these all that is found all around the world is GJB2 gene. Different types of mutations are found in GJB2 gene. Some of these mutations are non-sense while some are sense mutations. This study is focus on mutation in GJB2 gene and its prevalence in different region of the world. [ABSTRACT FROM AUTHOR]

Objective To investigate mutations in GJB2 in a consanguineous Iranian family with multiple members affected by non-syndromic hearing loss. Methods DNA was extracted from blood samples and the coding region of the conexin 26 gene was amplified using PCR. Bidirectional sequencing was carried out on PCR products. Results Direct sequencing of the PCR products led to the identification of a novel compound heterozygous mutation of c.551G>C/c.397T>G (p.R184P/p.W133G) and a previously reported homozygous mutation c.551G>C (R184P/R184P). Compound heterozygous mutation was identified in the father and his daughter and homozygous mutation was identified in his affected son. In silico analysis of p.W133G predicted mutation has deleterious effect on protein structure. Conclusion These results show the usefulness of GJB2 mutation screening and bioinformatic analysis for genetic diagnosis and counseling of non-syndromic hearing loss. [ABSTRACT FROM AUTHOR]

Objectives Mutations in the GJB2 gene encoding connexin 26 (Cx26) are major causes of hereditary deafness. This study aimed to characterize the mutation profiles of the GJB2 gene in a Chinese family with sensorineural hearing loss. Methods A Chinese family that included three individuals with sensorineural hearing loss and palmoplantar keratoderma underwent complete physical examinations, audiological examinations including pure tone audiometry and auditory brainstem response, skin pathological examination, and temporal CT scans. The entire coding region of GJB2, GJB3, GJB6, and the coding exons (exon7 + 8 and 19) of SLC26A4, mitochondrial 12SrRNA, and tRNA Ser (UCN) were sequenced. Structural analysis was performed to detect the effects of mutation on the tertiary structure of Cx26. Results A dominant GJB2 mutation, c.224G>A (p.Arg75Gln, p.R75Q), was detected in the family. No other mutation was identified in GJB2, GJB3, GJB6, or the coding exons (exon7 + 8 and 19) of SLC26A4, mitochondrial 12SrRNA, and tRNA Ser (UCN). Structural analysis revealed that the p.R75Q mutation likely affects the structural stability and permeation properties of the Cx26 gap junction channel. Conclusion Our findings provide further evidence of a correlation between the p.R75Q mutation in Cx26 and a syndromic hearing impairment with palmoplantar keratoderma. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To establish a high-throughput, low-cost method for neonatal genetic testing of the p.V37I of GJB2 gene, which is highly prevalent in East Asians and strongly associated with postnatal childhood hearing impairment. Methods: A total of 6460 newborn blood-spot DNA samples were screened by high-resolution melting analysis (HRMA). Results: The screening results were further verified by direct sequencing of 28 homozygous, 545 heterozygous and 200 wild-type samples. Conclusion: Our study indicated that the HRMA-based bloodspot screening method was of very high sensitivity and specificity and was suitable for large-scale screening of the p.V37I variants in newborns. [Copyright &y& Elsevier]

Abstract: Background: Hereditary sensorineural hearing loss (SNHL) is a genetically heterogeneous disorder worldwide. Mutations in the GJB2 gene are a frequent cause of hereditary SNHL. There is a prevalence of certain mutations in various populations which suggests that specific mutations may be influenced by ethnic background. Objective: To analyze the prevalence of GJB2, GJB6 mutations in several geographic areas of Mexico in patients with hereditary SNHL. Materials and methods: One hundred and forty Mexican unrelated propositi with prelingual SNHL were included in the study. All patients had three previous generations born in Mexico and belonged to no specific ethnic group. Analyses of the GJB2 and GJB6 genes and mt.1555AG mutation was not detected. Conclusion: We found a great variety of mutations depending on the analyzed region in patients with SNHL; 57.86% of patients had affection in one or two alleles in GJB2 or GJB6 genes whereas 42.14% were wild-type. In some cases, allele distribution depended on region. Molecular studies of more genes involved in hereditary non-syndromic SNHL are required to completely confirm the molecular basis of hearing loss in Mexican population. [Copyright &y& Elsevier]

Abstract: Objective: Mutations in GJB2 and GJB6 which comprise DFNB1 locus cause up to half of all cases of the prelingual autosomal recessive non-syndromic hearing loss (ARNSHL) worldwide. This study has intended to assess the spectrum and frequency of GJB2/GJB6 mutations in northwest of Iran. Methods: 508 Patients with presumed ARNSHL were analyzed by applying ARMS-PCR, SSCP, PCR-RFLP and sequencing assays. Results: Seventy-five (14.7%) different homozygous and eighty-seven (17.1%) different compound heterozygous genotypes were detected in this cohort. Concerning the GJB2 gene, c.35delG was the most prevalent mutation, accounting for 16.4% of the samples. In addition 29 sequence variations other than c.35delG mutation were distinguished in GJB2; namely, delE120, Ins A 290-291, R143Q, V37I, R32H, Y155X, V27I+T123N, F154F, 167delT, 312del14, 299-300delA, T8M, W24X, E114G+V27I, 235delC, R184P, V153I, S139N, A171T, M163V (unknown mutation), G127V, E147X, R127H, 35insG, R143W, V27I, G160S, E114G and IVS1+1G>A. Moreover, the IVS1+1G>A was accounted as a second common mutation. Conclusions: Overall, the frequency of GJB2 mutations (≥31%) is in agreement with other white population. These findings highlight the importance of the study of GJB2 gene in the diagnosis to provide early treatment and genetic counseling. [Copyright &y& Elsevier]