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Mutations in GJB2 (Gap junction protein beta 2) are the most common genetic cause of non-syndromic hereditary deafness in humans, especially the 35delG and 235delC mutations. Owing to the homozygous lethality of Gjb2 mutations in mice, there are currently no perfect mouse models carrying Gjb2 mutations derived from patients for mimicking human hereditary deafness and for unveiling the pathogenesis of the disease. Here, we successfully constructed heterozygous Gjb2+/35delG and Gjb2+/235delC mutant mice through advanced androgenic haploid embryonic stem cell (AG-haESC)-mediated semi-cloning technology, and these mice showed normal hearing at postnatal day (P) 28. A homozygous mutant mouse model, Gjb235delG/35delG, was then generated using enhanced tetraploid embryo complementation, demonstrating that GJB2 plays an indispensable role in mouse placenta development. These mice exhibited profound hearing loss similar to human patients at P14, i.e., soon after the onset of hearing. Mechanistic analyses showed that Gjb2 35delG disrupts the function and formation of intercellular gap junction channels of the cochlea rather than affecting the survival and function of hair cells. Collectively, our study provides ideal mouse models for understanding the pathogenic mechanism of DFNB1A-related hereditary deafness and opens up a new avenue for investigating the treatment of this disease. [ABSTRACT FROM AUTHOR]

To determine the prevalence of DFNB1 mutations containing GJB2 (connexin 26) genes with deletion 35delG mutation in congenital hearing loss, and to analyze this gene according to regional differences based on geographic and socio-economic relations in Turkish patients in Istanbul. Our study includes 51 unrelated children with non-syndromic sensorineural hearing impairment with the proof of clinical ABR results. Molecular studies were performed using PCR- Mediated Site-Directed Mutagenesis assay, PCR and direct sequencing to screen for GJB2 and 35delG mutations. Genomic DNA is obtained from the peripheral blood which is taken using a Qiagen DNA isolation kit. GJB2-35delG mutations were found in 25.5% of the patients; 19.6% were homozygous, 5.8% were heterozygous. The ratio of 35delG mutation detected in the children of families with consanguineous marriages and not; were 18.5% (n = 5) and 33.3% (n = 8) of cases respectively. The 35delG mutations in the patients whose father and mother were both from the Black Sea region were 43.18% (n = 19). Our results show that 35delG mutation is at a high frequency in our country, although it is more common in children of parents from the Black Sea region. Screening for the 35delG mutation in the GJB2 gene is the best choice for early diagnosis and emergency response plans for treatment and rehabilitation. [ABSTRACT FROM AUTHOR]

Gap Junction Beta 2 (GJB2) gene mutations are the leading causes of hereditary hearing impairment. This gene encodes various gap junction proteins such as connexin 26 (Cx26), which facilitate K+ homeostasis inside the cochlea in the inner ear. It is as well identified in non-syndromic deafness, which is not accompanied with other abnormalities in the body and contributes to 75% of the cases. The protein connexin 26 is composed of four transmembrane helices and two extracellular loops, in which each has three specific, highly preserved, cysteine residues held by intramolecular disulfide bridges. Moreover, 35delG and Cys169Tyr are the most common mutations of GJB2, where the former results in a shortened Cx26 protein due to the termination of coding sequence, and the latter leads to a destabilized protein structure as one of the three cysteine residuals that are affected. This short review gives further insights on how these two types of mutations lead to hearing loss.

OBJECTIVES: The aim of the present study was to investigate the presence of GJB2, GJB3, and GJB6 gene mutations in non-syndromic sensorineural hearing loss (NSHL) cases living in Sivas region, to provide appropriate genetic counseling for cases who were found to have mutation, and to contribute to decrease the frequency of mutant allele in the next generation and plan treatment and rehabilitation with early diagnosis. MATERIALS and METHODS: The study included 53 unrelated cases that were diagnosed with congenital NSHL between June 2009 and March 2010. Multiplex ligation-dependent probe amplification method was used for genotyping of GJB2, GJB3, and GJB6 gene mutations. RESULTS: Heterozygous 35delG variant was determined in 1.9% (n=1) of cases, homozygous 35delG in 15.1% (n=8), heterozygous IVS1+1G>A mutation in 1.9% (n=1), compound heterozygous in 3.8% (n=2), and homozygous IVS1+1G>A variant in 3.8% (n=2). None of the cases had mutation in GJB3 and GJB6 genes. Mutated allele frequencies in the present study were found to be 17.9% for 35delG and 6.6% for IVS1+1G>A. CONCLUSION: The present study showed that 35delG mutation is the most common variant in the Sivas region, and that IVS1+1G>A mutation should be investigated in hearing loss. Another result of the present study was that genetic analyzes would allow early diagnosis of hearing impairments particularly when infants whose parents have consanguinity do not pass the newborn hearing screening. [ABSTRACT FROM AUTHOR]

Background and Objectives: Mutations in the GJB2 gene are a major cause of hearing loss in many populations. A single mutation of this gene (c.35delG) accounts for approximately 70% of mutations in Caucasians with a carrier frequency of 2-4% in Europe. This study aims to determine the rate of c.35delG carrier frequency in the Middle East.Method: A systematic literature review of the PubMed, Google Scholar, Web of Science, and Science Direct databases was conducted for articles published before March 2019. The primary data of eligible studies including the number of samples, carrier frequency and so on were extracted.Results: Fourteen studies that involved 5,200 random controls from 15 populations of the Middle East were included and analyzed for the carrier frequency. The overall c.35delG carrier frequency was found to be 1.38% in the studied populations which is significantly lower than that identified in European populations, and also a west-to-east Middle Eastern gradient in the carrier frequency of c.35delG is suggested.Conclusion: This study shows the importance of establishing prevalence, based on the local population, for screening and diagnostic programs of live births. [ABSTRACT FROM AUTHOR]

Objective:This study was performed to investigate the GJB2 (connexin 26) gene mutations that are the most frequent cause of sensorineural deafness in patients with congenital non-syndromic sensorineural hearing loss in our region.Methods:Sixty patients [35 males (58.3%) and 25 females (41.7%)] between the age of 2-43 years (12.11±9.03) diagnosed with congenital non-syndromic sensorineural hearing loss were included in the study. The control group consisted of 60 individuals with similar demographic features having no hearing problems. 35delG, 167delT, delE120 and 235delC of GJB2 gene mutations and GJB6 gene mutations, and the presence of new mutations were also investigated by analysis of DNA sequences in all individuals.Results:Mutations were identified in 6 (10%) of the 60 patients in the study group. Five of these (8.3% of total) had 35delG and one (1.7%) had a delE120. No mutation was detected in control group individuals. In the study group, a statistically significant correlation was determined between the presence of familial sensorineural hearing loss history and 35delG or delE120 mutation (p=0.011, p=0.034).Conclusion:This is the first study which investigated the GJB2 gene mutation in our region, and our results indicate that 35delG mutation was the most frequent. We believe that our results are noteworthy for the identification of heterozygous or homozygous individuals and the genetic counseling of patients with congenital non-syndromic sensorineural hearing loss and their family.

Objective: Hereditary hearing loss (HHL) is a very common disorder. When inherited in an autosomal recessive manner, it typically presents as an isolated finding. Interestingly and unexpectedly, in spite of extreme heterogeneity, mutations in one gene, GJB2, are the most common cause of congenital severe-to-profound deafness in many different populations. In this study, we assessed the contributions made by GJB2 mutations and deletion in a portion of GJB6 to the autosomal recessive non-syndromic deafness genetic load in Iran. Materials & Methods: In this descriptive and cross – sectional study1605 probands from 1605 different nuclear families with autosomal recessive non-syndromic hearing loss were investigated. Hearing loss tests and clinical examination were done and 10 ml blood was drawn as DNA source. After study of 35delG mutation by ARMs PCR, negative or heterozygote individuals were sent to IOWA University for detection of other GJB2 mutations. Results: GJB2-related deafness was found in 243 families (15.1%). Conclusion: Varient geographic pattern for GJB2-related deafness has considerable results in Iran in comparable with other study in Europe and our neighboring countries and deletion in GJB6. [∆ (GJB6-D13S1830)] hasn't been detected in our studied population.

Introduction: Hearing loss is the most common sensory neural defect in humans, affecting 1 in 1000 neonates, with over half of these cases predicted to be hereditary in nature. Most hereditary hearing loss is inherited in a recessive fashion, accounting for approximately 80 % of non-syndromic hearing loss (NSHL). Mutations in GJB2 gene are major cause of inherited deafness in the European and American populations. To date, more than 90 mutations have been reported in this gene. Although most of these mutations are rare but 35delG mutation is the most common deafness causing allelic variant of GJB2 in most parts of the world. Methods: In this project, 120 probands from 120 families with ARNSHL in Yazd Province were studied. Mutations Screening of GJB2 was performed by Amplification Refractory Mutation System (ARMS)-PCR for detection of 35delG and then all samples excluding 35delG homozygote were analyzed by DHPLC and Direct Sequencing. Results: GJB2-related deafness was present in 7.5% of this population. We identified 4 mutations (35delG, 312del14, 314del14 and 167delT) and 4 polymorphisms (V153I, V27I, E114G and R127H) in this study. Conclusion: Prevalence of GJB2 mutations in this population was lower than American and European populations, and also other provinces of Iran. Interestingly, 312del14 rather than 35delG was the most common mutation found in the population under study. 56.25 % of GJB2 mutant alleles carried 312del14 mutation. To date, this frequency has not been reported in any of the world populations.

Congenital hearing loss with many genetic and environmental causes affects 1 in 1000 newborns. Mutations in the GJB2(Gap Junction Beta-2) gene encoding the gap junction protein connexin 26 have been established as the main cause of autosomal recessive non-syndromic hearing loss. The aim of this study was to study the frequency of one mutation (35delG) of GJB2 gene in Kerman non-syndromic deaf population. For this purpose, 130 chromosomes from 65 patients were studied and 35delG mutation was diagnosed in 3(2.3%) chromosomes (one patient was homozygote and the other one was heterozygote). This rate of frequency is significantly higher comparing to that in the whole population of Iran.

OBJECTIVE: To date, studies in all populations showed that mutations in the gene of Gap junction protein beta 2 (GJB2) play an important role in non-syndromic autosomal recessive congenital hearing loss. The aim of this study was to evaluate GJB2 gene of patients with hearing loss in our region using deoxyribonucleic acid (DNA) sequencing method and to demonstrate region-specific mutation and polymorphism distribution. MATERIALS and METHODS: Patients who had bilateral severe sensorineural non-syndromic hearing loss identified by audiologic evaluation were included. Peripheral blood samples were collected and the GJB2 gene exon1 and exon 2 regions were amplified by polymerase chain reaction (PCR). Obtained PCR products were sequenced by the DNA sequence analysis method (SeqFinder Sequencing System; ABI 3130; Foster City, CA, USA) and analyzed using the SeqScape software. RESULTS: Of the 77 patients, 16 had homozygous or heterozygous mutation. CONCLUSION: The mutation of 35delG, which is known as the most frequent mutation of GJB2 gene, was also the most frequently seen mutation at a ratio of 5.5% in patients with hearing loss in our region; this was followed by the V27I mutation. As this is the first study conducted by sequence analysis in our region, it was worth to be presented in terms of showing the distribution of mutation. [ABSTRACT FROM AUTHOR]

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]

Objective: This study was performed to investigate the GJB2 (connexin 26) gene mutations that are the most frequent cause of sensorineural deafness in patients with congenital non-syndromic sensorineural hearing loss in our region. Methods: Sixty patients (35 (58.3%) male and 25 (41.7%) female) between the age of 2-43 years (12.11±9.03) diagnosed with congenital non-syndromic sensorineural hearing loss were included in the study. The control group consisted of 60 individuals with similar demographic features having no hearing problems. 35delG, 167delT, delE120 and 235delC of GJB2 gene mutations and GJB6 gene mutations, and the presence of new mutations were also investigated by analysis of DNA sequences in all individuals. Results: Mutations were identified in 6 (10%) of the 60 patients in the study group. Five of these (8.3% of total) had 35delG and one (1.7%) had a delE120. No mutation was detected in control group individuals. In the study group, a statistically significant correlation was determined between the presence of familial sensorineural hearing loss history and 35delG or delE120 mutation (p=0.011, p=0.034). Conclusion: This is the first study which investigated the GJB2 gene mutation in our region, and our results indicate that 35delG mutation was the most frequent. We believe that our results are noteworthy for the identification of heterozygous or homozygous individuals and the genetic counseling of patients with congenital non-syndromic sensorineural hearing loss and their family. [ABSTRACT FROM AUTHOR]

GJB2 encodes connexin 26, a gap junction protein that is assumed to be a component of the potassium recycling pathway in the inner ear. Loss or malfunction of these gap junctions, as might be reflected by mutations in GJB2, may disrupt potassium movement from the hair cells through the supporting cell network to the endolymph, leading to hearing impairment. One mutation, the deletion of 1 guanosine residue from a stretch of 6 between nucleotide positions 30 and 35 (35delG) at codon 10, is the most common deafness-causing allelic variant of GJB2 in sporadic patients and autosomal recessive families. Mutations in the GJB2 gene represent the most common cause of autosomal recessive, sensorineural hearing loss. The 35delG mutation accounts for more than two-thirds of identified mutations. In this study, mutations, especially in the connexin 26 (GJB2), connexin 30 (GJB6), and 12srRNA genes, among 173 unrelated patients with prelingual nonsyndromic autosomal recessive deafness were screened and investigated by using the polymerase chain reaction-based restriction fragment length polymorphism (PCR-based RFLP), single-strand conformation polymorphism (SSCP), and sequence analysis methods. In patients with severe to profound hearing loss, 2 different mutations and 1 polymorphism (35delG and IVS1(+1)G→A mutations and V153I polymorphism) were found. The 35delG mutation was detected as the most common pathogenic allele among the Turkish patients and accounted for 50% of all mutant GJB2 alleles. The 35delG and IVS1+1G→A mutations in the Cx26 gene were detected with total allele frequencies of 16.47% and 4.33%, respectively, and the V153 polymorphism was found in a heterozygous state at an allele frequency of 3.47%. However, the 342-kb deletion in the Cx30 gene and mitochondrial (mt)1555A→G in the 12srRNA gene mutations could not be detected among the studied patients. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Determine the prevalence of 35delG mutation in GJB2 gene in patients with prelingual deafness of no defined etiology whose underwent cochlear implant in the Otolaryngology Department at the Hospital de Clínicas de Porto Alegre and compare the speech recognition index using an open-set of sentences according to the presence or absence of the 35delG mutation. Methods: Cross-sectional study nested in a cohort. Were analyzed 37 patients with indeterminate etiology for deafness that underwent to cochlear implant. DNA was extracted and the mutations were studied using Polymerase Chain Reaction followed by gene sequencing. Results: The prevalence of 35delG mutation was 11%. The speech recognition index was 72% in the group with 35delG mutation, and 30% in the group without this mutation (p >0.05). Conclusions: Prevalence of 35delG mutation in this study confirmed findings in the Brazilian literature. There was a clinically significant difference in hearing performance in patients with 35delG. Absence of statistical significance in this result might be attributed to the small number of patients with 35delG in our sample. [Copyright &y& Elsevier]

Sensor neural hearing loss (SNHL) is a complex disease with profound medical and social implications. About 1 in 1000 children are born with moderate to profound hearing impairment, and particularly on families that have no previous history of deafness, the diagnosis has a major impact. We investigated the family members with different degrees of deafness. The primary case was that of a child of 1 year and 6 months, diagnosed with severe bilateral sensor neural hearing loss. The family members, over three generations, have been investigated in terms of genetic mutations in the GJB2 gene (connexin26). 35delG mutation was identified in five family members, four as heterozygous form and primary case as homozygous form. The variability of the degree of hearing loss can be explained either by a different functional role of each mutated allele and its possible residual activity or by the possible interaction of environmental and genetic factors. [ABSTRACT FROM AUTHOR]

The authors present an important issue regarding congenital sensorineural hearing loss and the first study on connexin 26 performed in Romania, on a significant number of patients. We present the results from this study and the genetic correlation with the clinical aspects. Also, we compare our results with the results obtained in several studies performed in Western Europe countries. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Nonsyndromic hearing loss is one of the most abundant human sensory disorders, and can be found in 1 out of 1000 newborns. In 60–70% of the cases this disorder is hereditary. The phenotype varies from moderate hearing loss to almost complete deafness, often only revealed in late childhood. Early detection of hearing related genetic variations in the first few weeks of life would allow planning of the audiological and logopedical procedures to maintain the children''s normal audiological and speech development, and if required a cochlear implantation can be planned in time. We wanted to evaluate, whether the blood samples collected from neonates onto Guthrie cards (dried blood spots, or DBS), and blood collected from people of various ages into blood collecting tubes is equally usable for genetic testing. The quality of the samples on DBS''s for genetic tests after an extended period of storage was evaluated. The methods for sample preparation and analysis were also evaluated. Methods: Two DNA extraction methods were compared on the samples. We extracted DNA from whole blood with the Versagene Blood Kit from Gentra, and from DBS''s with boiling. Allele-specific PCRs (AS-PCR) were carried out on each sample. Samples were analyzed with AS-PCR and sequencing, for the 35delG mutation in the GJB2 (Cx26) gene. Freshly drawn and dried blood spot samples stored for several years were used in the experiments. Results: An AS-PCR method for detecting 35delG mutation on DNA extracted from Guthrie cards was validated. Blood samples up to 10 years of storage were applicable in the screen. 84 patients were found with 35delG mutations, both heterozygous (with no detected hearing related phenotypical discrepancies), and homozygous (phenotipically with moderate to severe hearing loss) forms. Conclusions: The dried blood spots on Guthrie cards require only three drops of blood to be collected from children, which causes less stress than taking 3ml of blood. The blood stored on Guthrie cards can be used to store DNA samples for at least 10 years. Even under suboptimal storage conditions the samples’ DNA remains intact for genetic testing. Compared to blood collection tubes Guthrie cards cost less, are easier to transport and store. [Copyright &y& Elsevier]

The article discusses a study that aims to evaluate the type and frequency of gap junction beta 2 (GJB2) gene mutations in Iranian patients with non-syndromic hereditary hearing loss (NSHHL). It notes mutations in connexin 26 are responsible for nearly 50% of autosomal-recessive hearing loss cases. Among the mutations that were diagnosed in 16 deaf patients are 35delG, R127H and a novel 355-357delGAG. According to the study, the most common deafness-causing mutation in the Iranian population is the 35delG mutation.

GJB2 mutations are major causes of autosomal recessive nonsyndromic hearing loss (ARNSHL) in many populations. However, a few mutations have an ethnic-specific background. We performed a review by means of a meta-analysis to evaluate the influence of the 35delG on ARNSHL. A PubMed, InterScience, British Library Direct, and Sciencedirect search using keywords '35delG', 'GJB2' and 'Connexin 26' associated with 'carrier frequency' was carried out to include all papers from February 1998 to February 2008. 35delG carrier frequencies in 23187 random controls were analysed and categorized, corresponding with geographical boundaries, from all over the world. Mean carrier frequencies of 35delG mutation were found to be 1.89, 1.52, 0.64, 1, and 0.64 for European, American, Asian, Ocean, and African populations, respectively. We found that the average 35delG carrier frequency is highest in southern Europe and lowest in eastern Asia. The south-to-north European gradient in the carrier frequency of 35delG was confirmed and also a west-to-east Asian gradient is suggested. This study highlights the importance of establishing prevalence, based on the local population for screening and diagnostic programs of live births. [ABSTRACT FROM AUTHOR]

Hereditary hearing loss (HL) is a very heterogeneous trait, with 46 gene identifications for non-syndromic HL. Mutations in GJB2 cause up to half of all cases of severe-to-profound congenital autosomal recessive non-syndromic HL, with 35delG being the most frequent mutation in Caucasians. Although a genotype–phenotype correlation has been established for most GJB2 genotypes, the HL of 35delG homozygous patients is mild to profound. We hypothesise that this phenotypic variability is at least partly caused by the influence of modifier genes. By performing a whole-genome association (WGA) study on 35delG homozygotes, we sought to identify modifier genes. The association study was performed by comparing the genotypes of mild/moderate cases and profound cases. The first analysis included a pooling-based WGA study of a first set of 255 samples by using both the Illumina 550K and Affymetrix 500K chips. This analysis resulted in a ranking of all analysed single-nucleotide polymorphisms (SNPs) according to their P-values. The top 250 most significantly associated SNPs were genotyped individually in the same sample set. All 192 SNPs that still had significant P-values were genotyped in a second independent set of 297 samples for replication. The significant P-values were replicated in nine SNPs, with combined P-values between 3 × 10−3 and 1 × 10−4. This study suggests that the phenotypic variability in 35delG homozygous patients cannot be explained by the effect of one major modifier gene. Significantly associated SNPs may reflect a small modifying effect on the phenotype. Increasing the power of the study will be of greatest importance to confirm these results.European Journal of Human Genetics (2009) 17, 517–524; doi:10.1038/ejhg.2008.201; published online 5 November 2008 [ABSTRACT FROM AUTHOR]

Abstract: In Caucasian populations a single mutation, 35delG, accounts for the majority of GJB2 gene mediated hearing loss, with carrier frequencies estimated between 2–4%, possibly resulting from a founder effect rather than from a mutational hot spot. In Moroccan population, the 35delG mutation accounts for 90.8% of all GJB2 mutated alleles in deaf patients with a carrier frequency of 2.65%. The aim of this study was to evaluate whether the 35delG mutation has derived from a single origin in the Moroccan population. We enrolled 30 unrelated deaf patients homozygous for the 35delG mutation and 165 unrelated control individuals negative for this mutation, and genotyped three microsatellite markers flanking the GJB2 region: D13S141, D13S175 and D13S143. Data analysis revealed that the 35delG mutation is associated with particular alleles of these markers, with significant linkage disequilibrium for the 125 and 105 nucleotide long alleles of D13S141 and D13S175, and that a single specific haplotype accounts for 68% of the chromosomes carrying the 35delG mutation. The estimate age of 35delG mutation is 135 generations or approximately 2700 years old. Like in other Mediterranean populations, our results suggest that in the Moroccan population the 35delG mutation has derived from a single origin in a common founder process. [Copyright &y& Elsevier]

Summary: Mutations of GJB2, the gene encoding connexin 26, have been associated with prelingual, sensorineural hearing loss of mild to profound severity. One specific mutation, the 35delG, has accounted for the majority of mutations detected in the GJB2 gene in Caucasian populations. Recent studies have described progression of hearing loss in a proportion of cases with GJB2 deafness. We report an unusual family with four 35delG homozygous members, in which the parents were deaf-mute whilst both children had a postlingual progressive hearing loss. Furthermore, the son suffered from sudden hearing loss. [Copyright &y& Elsevier]

Serial audiograms were analysed for seven subjects, who were homozygous for the 35delG GJB2 mutation. The criterion for determining progression of hearing loss was at least a 1-dB loss in air conduction pure-tone average-3 (ACPTA-3) or ACPTA-4 per year for 2 to 10 years, with a minimum change of 10 dB ACPTA 3 or 4. Bilateral progression of hearing loss was found in 43% (3/7) of the subjects. A meta-analysis of seven studies with non-overlapping data sets and similar ascertainment criteria indicated that 19% of DFNB1 subjects with GJB2 mutations have progressive hearing loss. These data suggest that it may be incorrect to assume that congenital hearing loss due to this mutation is stable. We recommend rigorous audiologic surveillance for individuals with DFNB1. [ABSTRACT FROM AUTHOR]

Summary: Objective: DFNB1 locus has been reported as a major cause of autosomal recessive non-syndromic hearing loss (ARNSHL) worldwide. 35delG and del(GJB6-D13S1830) are thought to be two common mutations in this locus among Caucasians. The aim of this study is to determine the significance of these two mutations in aetiology of ARNSHL in Iran. Methods: One hundred and thirty-three unrelated patients with ARNSHL were tested by using multiplex allele-specific PCR assay after validation by positive control samples. Results: The frequency of 35delG was about 18.5%, however, del(GJB6-D13S1830) was not found in the studied patients. Parental consanguinity was observed in 50% of 35delG-mutated families. Conclusions: Our results support founder effect regarding these mutations. [Copyright &y& Elsevier]

Summary: Objective: Mutations in the GJB2 gene are a major cause of autosomal recessive and sporadic non-syndromic hearing loss in many populations. A single mutation of this gene (35delG) accounts for approximately 70% of mutations in Caucasians with a carrier frequency of 2–4% in Europe. This study aims to determine the rate of 35delG carrier frequency in Iran. Methods: Genomic DNA was extracted from a total of 550 unaffected unrelated subjects from 4 provinces of Iran following the standard phenol chloroform procedure. The one base pair deletion (35delG) was analysed using a nested PCR procedure; 35delG mutation carriers were subsequently confirmed by sequence analysis. Moreover, using the Binomial probability distribution, we compared the 35delG carrier frequency of Iranian population with the various Middle Eastern and overall European populations. Results: Of the four populations studied, we found a high carrier frequency of 2.8% in Gilan province in the north of Iran. The overall 35delG carrier frequency was found to be 1.25% in the populations studied (our present and previous data) which is similar to the overall 35delG carrier frequency detected in Middle Eastern populations, but Significantly lower than that identified in European populations. [Copyright &y& Elsevier]

Abstract: Mutations of the connexin 26 gene, GJB2, are the most common cause of non syndromic autosomal-recessive hearing loss. One of the GJB2 mutations, the 35delG, is recurrent in European and Mediterranean populations with allelic frequency of at least 70% in patients with hearing loss caused by GJB2 impairment. Objectives: To determine the prevalence of the 35delG mutation in non-syndromic autosomal-recessive deafness in Morocco. Patients and methods: We looked for the 35delG mutation among 25 non-related Moroccan children suffering from an autosomal recessive hearing loss. A screening for GJB2 mutations, and then a search for GJB6 deletions were carried out among patients who do not bear the 35delG. Results: Twelve patients were homozygous for the 35delG mutation. This mutation was responsible for almost half of the hearing loss among our patients (48%). There was no other GJB2 or GJB6 mutation among 13 patients. Conclusion: This study underlines the advantages of a systematic search for this mutation among deaf children when environmental causes are considered irrelevant. The identification of this genetic anomaly signs the etiologic diagnosis of deafness, which allows a relevant genetic advice, and a better treatment of patients. [Copyright &y& Elsevier]

Summary: Objective: Hearing loss is a complex multifactorial disorder caused by genetic and environmental factors. The 35delG mutation in the GJB2 gene is the most prevalent mutation in Caucasian patients with genetic sensorineural deafness. The A1555G mutation in the mitochondrial 12S rRNA is the main genetic alteration associated with aminoglycoside-induced deafness. The aim of this study was to evaluate the prevalence of both mutations in general population of Argentina. Methods: A total of 712 samples of unrelated healthy blood donors and 330 newborn dried blood spots were studied by PCR–RFLP. Results: The 35delG mutation was detected in 11/ 712 unrelated blood donors. The carrier frequency found in this sample (1/65) proved to be lower than that found in Southern European countries, mainly Spain and Italy, from where Argentina originally received its major immigration waves. When the populations of Southern Europe were considered altogether, this difference reached statistical significance. The A1555G mutation was not found in any of the 1042 samples tested. Conclusions: Taking into account the 35delG carrier frequency found in this study, it could be estimated that 130–160 children with congenital deafness due to mutations in the connexin genes would be born per year in Argentina. In contrast, the mitochondrial mutation A1555G appears to be infrequent in general Argentinean population. [Copyright &y& Elsevier]

Summary: Objective: Mutations in the GJB2 (connexin-26) gene are responsible for more than half of all cases of prelingual recessive inherited non-syndromic deafness in Europe. One specific mutation 35delG, accounts for up to 70% of the mutations detected in European populations and is one of the most frequent disease mutations identified so far. The aim of this study is to determine the percentage of carriers of this mutation in the Greek Cypriot population. Methods: Genomic DNA was isolated from a total of 405 healthy unrelated Greek Cypriot adults. Screening for the frameshift 35delG mutation was performed by using an allele-specific PCR protocol. Moreover, using the Poisson probability distribution, we compared the carrier frequencies of the 35delG mutation of the Greek Cypriot population to the various European and Middle Eastern populations. Results: The carrier frequency in the Greek Cypriot population was estimated to be 2.5% and is similar to that observed in other European populations. The variance estimate for 35delG mutation produces slightly wider intervals with the Poisson model when compared with Binomial probability variance estimate. [Copyright &y& Elsevier]

Mutations in GJB2 , the gene encoding the protein Connexin 26, have been shown to account for as much as 50% of autosomal recessive, non-syndromic childhood hearing loss (ARNSHL). Early, correct diagnosis and intervention have greatly improved the possibilities for these children in learning and developing language skills. In recent years, many reports from varied parts of the world have described the local scene of mutations in Connexin 26. The prevalence differs with geographic location and assessment procedures. Mutations in Connexin 26 have until recently been identified in very few cases in Sweden, Norway and Denmark, and nationwide population samples have not been studied in the Scandinavian countries. In this study we present the results of a large nationwide and a regional study of the prevalence of the 35delG, L90P and 167delT mutations of the GJB2 gene in Sweden. A total of 2052 samples (dried blood spots) were analysed. 1501 samples were collected representing all of Sweden and 551 samples from northern Sweden. The allele frequencies in Sweden were found to be 35delG, 0.83%; L90P, 0.30%; and 167delT, 0%. The prevalence of mutations in Connexin 26 in Sweden seems to be comparable to that in other northern European countries. [ABSTRACT FROM AUTHOR]

Abstract: Mutations in the connexin 26 gene (GJB2) cause a significant proportion of prelingual non-syndromic autosomal recessive deafness in all populations studied so far. To determine the percentage of hearing loss attributed to GJB2 in northeast Turkey, 93 unrelated patients with autosomal recessive non-syndromic hearing loss (ARNSHL) were screened. Seven different mutations were found in 29 of the patients with severe to profound hearing loss. The 35delG mutation was the most common mutation, accounting for 76% of all mutant GJB2 alleles. Four already described mutations, W24X, 310del14, delE120 and R184P and two novel mutations, Q80K and P173S, were identified. The allelic Δ(GJB6-D13S1830), which can cause hearing loss in combination with GJB2 mutations, was not present in our patients. Our results are comparable to those reported in other regions in Turkey and indicate that GJB2 mutations account for about 30% of Turkish patients with ARNSHL. Besides 35delG, W24X and delE120 occur more than once in the Turkish ARNSHL population with a frequency of about 5%. [Copyright &y& Elsevier]

Recent advances in the molecular biology of hearing and deafness are being transferred from the research laboratory to the clinical arena. This transfer of knowledge will enhance patient care by making the diagnosis of hereditary deafness easier; however physicians and audiologists must clearly identify that subset of the deaf and hearing populations best served by this knowledge. It is also essential for physicians and audiologists to understand the limitations of genetic testing for deafness, and it is imperative that these limitations be appropriately explained to patients and their families.: Learning outcomesThe reader will be introduced to the concept of genetic testing for deafness. Two genes that make appreciable contributions to the autosomal recessive non-syndromic deafness (ARNSD) genetic load will be reviewed, GJB2 and SLC26A4. In addition, the unique aspects of genetic counseling for deafness and recurrence chance estimates are explained. [Copyright &y& Elsevier]

Objective Mutations of the gap junction beta 2 (GJB2) gene coding for the protein connexin 26 account for up to 50% of nonsyndromic sensorineural hearing loss (NSHL), with specific mutations associated with distinct ethnic groups. A biracial family with nonsyndromic sensorineural deafness consistent with autosomal recessive inheritance was examined for connexin 26 (Cx26) mutations. Study Design Prospective observational study. Methods A family consisting of a Caucasian mother and a Chinese father with two of six children affected by NSHL was examined for Cx26 mutations. Peripheral blood lymphocyte DNA was used to amplify by polymerase chain reaction the Cx26 coding region, followed by mutation detection enhancement gel screening and complete sequencing. Phenotypic characterization using audiometric testing was completed for all children and both parents. Results The two affected children were found to be compound heterozygotes for Cx26 mutations, displaying a previously unreported combination of 35delG and 235delC. The parents were each unaffected heterozygotes consistent with their ethnic heritage, specifically, the Caucasian mother a 35delG heterozygote and the Chinese father a 235delC heterozygote. Conclusions Connexin 26 mutations account for a significant proportion of NSHL worldwide, with specific mutations linked to distinct ethnic groups. Genetic analysis of a biracial family with NSHL revealed a novel 35delG/235delC compound heterozygous state in phenotypically affected children. These results highlight the usefulness of Cx26 mutation screening for genetic counseling and suggest that the 235delC mutation is present in China as it is in Japan and Korea. [ABSTRACT FROM AUTHOR]

Congenital deafness occurs in approximately 1 in 1000 live births. In developed countries about 60% of hearing loss is genetic. However, in Brazil most cases of hearing loss are due to environmental factors, such as congenital infections (mainly rubella), perinatal anoxia, kernicterus and meningitis. Recently, it has been demonstrated that the GJB2 gene is a major gene underlying congenital sensorial deafness. Mutations in this gene cause 10–20% of all genetic sensory hearing loss. One specific mutation, 35delG, accounts for the majority of mutant alleles. The extent of the hearing impairment varies from mild/moderate to profound, even within the patients homozygous for the common 35delG mutation. There may also be progression with age. Mutation analysis in the GJB2 gene was performed on 36 families (group A) presenting with at least one individual with non-syndromic deafness (NSD). An unselected series of 26 deaf individuals referred by other services where the environmental factors were not completely excluded was also part of the study (group B). Mutations in the GJB2 gene were found in 22% (eight patients) of the families tested in group A, and 11.5% (three patients) of individuals within group B. This finding should facilitate diagnosis of congenital deafness and allow early treatment of the affected subjects. [ABSTRACT FROM AUTHOR]

The 35delG mutation in the connexin 26 gene (GJB2) at the DFNB1 locus is the most common mutation in patients with autosomal-recessive sensorineural deafness. Genetic diagnosis is crucial for genetic counseling. We have developed an easy and simple method and screened a total of 235 unrelated hearing-impaired children. We found 48 of the subjects to be homozygous for the mutation, including 27 of 83 familial cases, 15 of 101 singletons, 4 of 9 subjects born to assortative marriages (deaf married to deaf), and 2 of 42 subjects for whom the parents claimed an environmental factor as the etiology of the condition. The high ratio of individuals homozygous for the mutation indicated that the 35delG mutation in the connexin gene accounts for more than 90% of the mutations at this locus. [ABSTRACT FROM AUTHOR]

Fifty to eighty percent of autosomal recessive congenital severe to profound hearing impairment result from mutations in a single gene, GJB2, that encodes the protein connexin 26. One mutation of this gene, the 3SdelG allele, is particularly common in white populations. We report evidence that the high frequency of this allelic variant is the result of a founder effect rather than a mutational hot spot in GJB2, which was the prevailing hypothesis. Patients homozygous for the 35delG mutation and normal hearing controls originating from Belgium, the UK, and the USA were genotyped for different single nucleotide polymorphisms (SNPs). Four SNPs mapped in the immediate vicinity of GJR2, while two were positioned up to 76 kb from it. Significant differences between the genotypes of patients and controls for the five SNPs closest to GJR2 were found, with nearly complete association of one SNP allele with the 3SdelG mutation. For the most remote SNP, we could not detect any association. We conclude that the 3SdelG mutation is derived from a common, albeit ancient founder. [ABSTRACT FROM AUTHOR]

The knowledge about gene mutations causing permanent hearing impairment (HI) is rapidly increasing, offering clinicians the possibility of analysing different gene mutations in relation to various phenotypes. This study examines a possible relationship between U-shaped audiograms and mutations in the GJB2-gene, coding for Connexin 26 (Cx 26). Thirty-eight subjects at a median age of 42 years, range 18–60 years with symmetric U-shaped audiograms classified as sensorineural were included in the genetic investigation. The gender distribution was 13 males and 25 females. No subjects had any indication of syndromic HI, and any possible exogenous factor that might cause HI was excluded. Three subjects had self-reported prelingual HI and 34 subjects had self-reported postlingual HI. Thirty-five subjects had one or more family members with HI. In 19 subjects the entire Cx 26 gene was examined, whereas 19 subjects were investigated for the 35delG mutation only. One female with mild HI and postlingual onset of the HI was heterogeneous for the L90P-mutation in the Cx 26 gene. In all other subjects no mutations in the Cx 26 gene could be identified. Mutations of the Cx 26 gene are very rare among subjects exhibiting a U-shaped phenotype of the audiogram. However the majority of the investigated subjects (35/38) had a family history of HI and it seems therefore reasonable to ascribe U-shaped hearing deficit to genetic factors which has to be searched for in alternative gene mutations. [ABSTRACT FROM AUTHOR]