35delG Mutation Research Articles

Unusual phenotype in 35delG mutation: a case report

BackgroundMutations in the GJB2 gene, which encodes the protein connexin 26 and is involved in inner ear homeostasis, are identified in approximately 50% of patients with autosomal recessive nonsyndromic hearing loss, making it one of the primary causes of prelingual nonsyndromic hearing loss in various populations. The 35delG mutation, one of the most common mutations of the GJB2 gene, usually causes prelingual, bilateral mild to profound, nonprogressive sensorineural hearing loss.Case presentationWe present an unusual case of an 18-year-old Turkish female with heterozygous 35delG mutation and postlingual, profound-sloping, progressive and fluctuating unilateral sensorineural hearing loss. The phenotype is different from the usual findings.ConclusionsThe 35delG mutation causing hearing loss may not always be reflected in the phenotype as expected and therefore may have different audiologic manifestations.

Pathogenic variant c.35delG of the GJB2 gene associated with nonsyndromic prelingual deafness

Introduction: the pathogenic variant c.35delG of the GJB2 gene is the most frequently observed in all populations, associated with nonsyndromic autosomal recessive prelingual prelingual sensorineural deafness, since 2001 is available in the National Network of Medical Genetics the study of this mutation. Objective: to describe the presence of the pathogenic variant c.35delG of the GJB2 gene associated with nonsyndromic prelingual deafness, with evidence of autosomal recessive inheritance. Methods: a descriptive cross-sectional study was carried out on 379 cases registered with isolated prelingual hearing loss between 2001 and 2023; for the identification of the c.35delG mutation, the polymerase chain reaction technique was used, with enzymatic digestion, and its genotype and frequency were described. Results: the pathogenic variant c.35delG of the GJB2 gene was found in 121 of those studied (31,91 %), 59 in homozygosis and 62 in heterozygosis. The allele frequency found among the positive cases was 0,743. Conclusion: the pathogenic variant c.35delG in individuals with nonsyndromic prelingual deafness of possible autosomal recessive inheritance is found in a high proportion

Unraveling the Diversity of GJB2 Mutations in Nonsyndromic Hearing Loss: A Comprehensive Study in the Moroccan Population

Introduction: Despite the high genetic heterogeneity of hearing loss, mutations in the GJB2 gene are a major cause of autosomal recessive nonsyndromic hearing loss (NSHL) worldwide. However, the mutation profile of GJB2 in NSHL is under-investigated in Morocco, especially among simplex cases. This study aimed to identify the spectrum and frequency of GJB2 mutations in the Moroccan population among simplex and multiplex families with NSHL. Methods: Moroccan families with NSHL were selected according to well-defined criteria. Selected families were screened for GJB2 gene variants using direct sequencing of the entire coding region of GJB2. Results: A total of 145 affected individuals from 115 families with NSHL were included in this study (49 simplex, 66 multiplex). Mutations in the GJB2 gene were noted in 28.69% of the families (33/115), of which 75.75% were multiplex families and 24.24% were simplex. In total, seven different mutations were detected: c.35delG(p.G12fs), c.551G>A(p.R184Q), c.139G>T(p.E47X), c.109G>A(p.V37I), c.167delT(p.L56fs), c.617A>G(p.N206S), c.94C>T(p.R32C). The last three mutations have not previously been reported in Morocco. The most common GJB2 mutation was c.35delG (21.73%), followed by p.V37I (2.60%) and p.E47X (1.73%). Conclusions: Our study confirms a high prevalence of GJB2 variants in the Moroccan population, particularly the c.35delG mutation. Additionally, we have identified previously unreported or rarely reported mutations, revealing a greater diversity of GJB2 mutations. These findings emphasize the importance of comprehensive screening beyond the 35delG mutation for patients with NSHL, regardless of their family history. Integrating this approach into clinical care will enhance diagnosis and management of hearing loss in the Moroccan population.

Assessment of the risk of hearing loss in children with cystic fibrosis

Cystic fibrosis (CF) is a severe hereditary disease with a multisystem lesion. Manifestations of CF include severe infectious purulent lesions of all parts of the respiratory tract, including purulent rhinosinusitis with nasal polyps. The involvement of the sinonasal region and the need for systemic use of ototoxic drugs (primarily aminoglycosides to treat resistant bacterial infection) potentially create a risk of both conductive and sensorineural hearing loss (SNHL). The available data on the epidemiology of hearing disorders in CF is contradictory. Currently, genetic determinants of the development of aminoglycoside SNHL have been identified. For 136 CF patients (75 girls, 61 boys) aged 3 to 17 (9.4±3.9) years were performed audiological examination: tympanometry, transient-evoked otoacoustic emission and the pure tone threshold audiometry (standard frequency range) (n=126). History of systemic therapy with aminoglycosides was evaluated for each patient. Sequencing of c.35delG mutations in the GJB2 gene (nuclear DNA) and A1555G in the 12S rRNA gene (mitochondrial DNA) was performed in 215 patients with cystic fibrosis (the group partially overlaps with the audiological group), and as a control - 106 children with bronchial asthma and 103 healthy children, their age ranged from 3 to 17 (8.8±3.8) years. Audiological examination of CF children reveled a prevalence of conductive hearing loss comparable to the general population (2.4%). The frequency of SNHL was 1.6%, wich exceeds that of non-CF children. A genetic study revealed one case of heterozygous carriage of the c.35delG mutation in the GJB2 gene in a patient with bronchial asthma. In the group of patients with CF (n=215), mutations in the connexin 26 gene were not detected. No A1555G mutation was detected either in the group of patients with CF or in the control groups. Children with CF are at risk for the development of sensorineural, but not conductive hearing loss. Routine total screening for A1555G and c.35delG mutations probably seems not to be recommended.

The pathogenesis of common Gjb2 mutations associated with human hereditary deafness in mice

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.

Connexin 26 (GJB2) Mutations Associated with Congenital Hearing Loss in a Country of Different Migration Routes: Turkey.

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.

Identification of GJB2 Variants in 75 Unrelated Iranian Autosomal Recessive Non-syndromic Hearing Loss Patients

Background: Hearing loss (HL) is the most prevalent sensory disease in humans. HL is among the most clinically and genetically heterogeneous disorders. Pathogenic variants in GJB2 are the principal cause of HL in many populations. Therefore, GJB2 analysis should be considered as the first step for HL. Objectives: This study aimed to find causative variants in the GJB2 gene in 75 unrelated Iranian patients who suffered from Autosomal recessive non-syndromic hearing loss (ARNSHL). Methods: Peripheral blood samples were used for genomic DNA extraction. PCR-direct sequencing was performed to detect GJB2 mutations. Results: In this study, thirty-four chromosomes (21.33%) carried GJB2 mutations. In general, 10 variants were detected among 19 patients. Seven cases were homozygous for c.35delG; (p.Gly12Valfs*2), two were homozygous for c.71G>A; (p.Trp24*), two were homozygous for c.358-360delGAG (p.Glu120del), and two were homozygous for c.-23+1G>A mutation. One patient was a compound heterozygote for c.35delG and c.-23+1G>A mutations, and another patient with compound heterozygosity for c.290dupA and c.235delC mutations were determined. Four patients carried a mono-allelic variant in the GJB2 including c.126G>T; (p.Glu42Asp), c.23C>T; (p.Thr8Met), c.445G>A; (p.Ala149Thr) and c.269T>C; (p.Leu90Pro). Accordingly, c.35delG mutation was the most common variant in this study. Conclusions: Finding common variants of HL mutations in different populations can elevate the diagnostic value of molecular testing in the screening of affected individuals, and can improve counselling to minimize the risk of having affected offspring for at-risk couples. Besides, early diagnosis can easily lead to speech development and prevents further problems.

КОМПЛЕКСНАЯ ДИАГНОСТИКА СЛУХА У ДЕТЕЙ С ЗАБОЛЕВАНИЕМ СПЕКТРА АУДИТОРНЫХ НЕЙРОПАТИЙ В РЕСПУБЛИКЕ БЕЛАРУСЬ

Auditory Neuropathy Spectrum Disorders, ANSD is a state of the auditory system in which the patient has otoacoustic emissions (OAEs) and/or cochlear microphonic potential (CMP), and auditory brainstem responses (ABRs) are absent or significantly reduced. In contrast to sensorineural hearing loss, where the outer and inner hair cells of the cochlea are damaged, in ANSD the outer hair cells are preserved. The complexity of ANSD detection and the variety of clinical symptoms of this disorder make it difficult to differentiate this disease from sensorineural hearing loss. Purpose. Improvement of the differential diagnosis of ANSD and sensorineural hearing loss by defining the main anamnestic and audiological criteria. Materials and methods. The research included 2 groups of patients: the core group - 48 patients with bilateral ANSD and the control group - 30 patients with bilateral chronic sensorineural hearing loss. All patients underwent assessment of the anamnesis data, impedance measurement, tone threshold audiometry, registration of OAE (TEOAE), registration of ABR with allocation of CMP, registration of stationary auditory evoked potentials. Results. In patients with ANSD the incidence of prematurity, low birth weight, and hyperbilirubinemia is significantly higher (p <0.05) than in patients with sensorineural hearing loss. In patients with ANSD the 35delG mutation in the GJB2 gene was not identified, in contrast to patients with sensorineural hearing loss (genetic factor was confirmed in 23.3%) (p <0.05). Newborn hearing screening on both sides was conducted in 15 children (31.3%) with ANSD and only 1 child (3.3%) with sensorineural hearing loss (p <0.05). In 8 patients (16.7%) with ANSD was recorded TEOAE during the initial audiological diagnosis, in contrast to sensorineural hearing loss (TEOAE was not recorded in 100% of patients) (p <0.05). In contrast to sensorineural hearing loss, the ABR thresholds in ANSD did not correspond to the behavioral hearing thresholds. CMP was recorded on the right and left ear in all patients (100%) with ANSD and remained unchanged during the observation process, in contrast to patients with sensorineural hearing loss, in whom CMP was not recorded on both sides (p <0.05). Conclusions. The structure of the main risk factors for hearing loss in children with ANSD and sensorineural hearing loss is different. In the differential diagnosis with sensorineural hearing loss, the possibility of TEOAE disappearance in ANSD should be taken into account. Registration of ABRs with the allocation of CMP is the most informative method of ANSD diagnostics. CMP registration should be conducted for all patients who do not have ABR peaks at the maximum stimulus intensity, regardless of the OAE registration results.

Prevalence of GJB2 gene mutations correlated to presence of clinical and environmental risk factors in the etiology of congenital sensorineural hearing loss of the Romanian population.

Although etiologically heterogeneous at least 50% of all early on-set hearing losses have a genetic cause and of these, the large majority, 75-80% are most probably autosomal recessive and 70% are non-syndromic. The rest of the congenital hearing losses are determined by clinical and environmental factors such as ototoxic medication, prematurity, and complications at birth. During the last decade it became clear that 50-80% of all such afflictions result from mutations in a single gene, GJB2, which encodes the protein Connexin 26. In order to, at least partially clarify this problem, especially in an emerging country such as Romania, where the problem is not studied adequately, we developed a comprehensive study of genetic, clinical and environmental risk factors for congenital hearing loss. The two most common variations of this gene, 35delG and W24X in children with positive diagnosis of bilateral severe to profound sensorineural hearing loss were investigated. A cohort of 34 children (20 female and 14 male), ages between 2 and 10 (mean age 4.62 years), coming from 33 non-related families were evaluated. All cases were diagnosed with severe or profound bilateral congenital SNHL. A statistical comparison of genetic and environmental/clinical prevalence was also attempted since the presence of a genetic disorder cannot rule out the role of other documented risk factors in the etiology of SNHL. The results showed that, 29.4% of cases (10/34) were homozygotic for the 35delG mutation 35delG/35delG), also known as genotype Δ/Δ. 5.88% of cases (2/34) belong to the heterozygotic bi-genic group 35delG/W24X. The clinical factors with high statistical significance for SNHL in a non-genetic group have no significance for genetic SNHL patients. Thus, the present study confirms the relatively high prevalence of the 35delG and W24X mutations in cases of congenital non-syndromic severe of profound bilateral SNHL.

The frequency of the homozygote 35delG mutation in the connexin 26 gene in North African with non-syndromic hearing loss: A meta-analysis study

ObjectiveEstimate the frequency of the homozygote 35delG mutation in patients with non-syndromic hearing loss. DesignMeta-analysis of studies investigated the presence of the 35delG mutation in patients from the North of Africa (Morocco, Algeria, Tunisia, Libya and Mauritania). We used three databases for seeking studies that reported the frequency of the 35delG mutation between 2000 and 2020. We excluded studies if they disagree with the inclusion criteria. Study samplePatients from the North of Africa with non-syndromic hearing loss. ResultsWe included 12 studies with a total of 1052 patients with non-syndromic hearing loss. The 35delG mutation was found in 303 (28.80%). ConclusionThe research of 35delG mutation is very useful in the investigation of the genetic etiology of non-syndromic hearing loss. However, including other gene candidates will be better for the identification of the etiology of hearing loss in patients negative for the 35delG mutation.

Investigating GJB2 Mutation in 31 Individuals With Non-syndromic Hearing Loss

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

Genetic Screening for 35delG Mutation in Egyptian Patients with Profound Sensorineural Hearing Loss Scheduled for Cochlear Implantation: A Population-Based Study

Objectives: The aim of this work was to assess the type and site of the 35delG gene mutation in patients presenting with profound SNHL and scheduled for cochlear implantation. The secondary objectives were to determine their geographical distribution throughout Egypt, screening of the parents for the mutation, and to correlate the type of mutation with clinical severity and outcomes after surgery. Methods: The study was carried out on 100 consecutive patients scheduled for cochlear implantation. Patients with syndromic hearing loss or noncongenital hearing loss (trauma, infections, and ototoxicity) were excluded. All patients were subjected to detailed history taking including geographic tagging for their origins in Egypt, imaging (CT and MRI cochlear implantation protocols), full audiological evaluation (PTA, ABR, and TEOAE), and genetic screening for GJB2 mutation using Invitrogen PCR mix and ApaI restriction enzyme (North America, CA, 10572-014). The parents of mutation-positive patients were also subjected to audiological and genetic analysis. All patients were subjected to postimplantation evaluation of hearing after 6 and 12 months. Results: There were 64 males and 36 females from 98 families. Ages ranged between 1.9 and 7 years (mean 3.72 years). They originated from all over Egypt but the majority came from the Giza and Cairo areas. The 35delG mutations were found in exon 2 in 31% of the cases and all were heterozygous. In the parents, 18 mothers and 13 fathers were positive but only 8 had mild to moderate SNHL. Hearing evaluation by pure tone and speech discrimination scores at 6 and 12 months showed that the 35delG children had a statistically better result compared to the children without this mutation. Conclusion: The prevalence of the 35delG mutation in nonsyndromic children in this sample was 31% which is different from previous studies in the Egyptian population but close to the values found in other populations in the Mediterranean basin.

Etiology of early hearing loss in Brazilian children

IntroductionHearing loss etiology depends on the population studied as well as on the ethnicity and the socio-economic condition of the analyzed region. Etiological diagnosis contributes to the improvement of preventive measures and to the early identification of this deficiency. ObjectiveTo identify the etiological factors of hearing loss and its prevalence in a tertiary hospital in southern Brazil, to verify the frequency of mutations in GJB2 and GJB6 genes, and to correlate the degree of hearing loss with the etiological factors of deafness. MethodsThis prevalence study involved 140 children with bilateral sensorineural or mixed hearing loss. Medical history, physical examination, audiometry, and evoked auditory brainstem response were conducted. Imaging and genetic examinations were also performed. ResultsEtiologies and their prevalence were as follows: (a) indeterminate causes, 31.4%; (b) conditions related to neonatal period, 22.1%; (c) genetic, 22.1%; (d) auditory neuropathy, 10%; (e) other factors (cortical malformation, intracranial hemorrhage, and internal ear malformations), 7.9% and (f) congenital infections, 6.4%. Within the genetic cases, ten homozygous and seven heterozygotes of the 35delG mutation were identified, besides two cases of rare variants of GJB2: p.Try172* and p.Arg184Pro. One case with homozygosis of del(GJB6-D13S1830) was found. Regarding severity of hearing loss, in 78.6% of the cases the degree of hearing loss was profound and there were no significant differences when comparing between etiologies. ConclusionThe number of indeterminate etiologies is still high and congenital CMV infection may be a possible cause of undiagnosed etiology for hearing loss. The predominance of etiologies related to neonatal conditions and infectious causes are characteristic of developing countries. The most prevalent mutation was 35delG, the main GJB2 gene, probably because of the European influence in the genotype of our population.

Audiological features in Serbian patients with hearing impairment identified with c.35delG in the GJB2 gene

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.

Connexin 26 (GJB2) gene mutations linked with autosomal recessive non-syndromic sensor neural hearing loss in the Iraqi population.

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

Prevalence of 35delG mutation in GJB2 gene in the Moldavian population

Prevalence of 35delG mutation in GJB2 gene in the Moldavian population

Мутации в гене GJB2 у детей с двусторонней тугоухостью в Кыргызстане

The purpose of this work was to identify and study the prevalence of mutations in the GJB2 gene encoding the connexin 26 protein in the Kyrgyz Republic. Hearing loss is currently the most widespread disease. This paper presents a study of 89 patients with persistent bilateral sensorineural hearing loss and deafness of unknown etiology. All patients were divided into two groups. One group included patients with an unburdened family history, the second group included patients with a burdened family history. When clarifying the etiology of the disease, we can assume further dynamics of the hearing thresholds, as well as select the necessary tactics for managing such patients for early rehabilitation. As a result of molecular genetic research, mutations in the GJB2 gene were detected in 19 patients (21,3%). The 35delG mutation was found in a homozygous state in 5 children from parents of Russian and Tatar origin. In 4 families, parents were in an assorted marriage. Among 62 Kyrgyz, mutations in the GJB2 gene were detected in 9 cases, which accounted for 14,5% of cases. The 35delG mutation among the Kyrgyz was found only in the compound heterozygous state with the 235delC mutation in 3 children and with the –23 + 1G> A mutation in one child.

The Analysis of GJB2, GJB3, and GJB6 Gene Mutations in Patients with Hereditary Non-Syndromic Hearing Loss Living in Sivas.

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. 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. 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. 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.

First-Line Molecular Genetic Evaluation of Autosomal Recessive Non-Syndromic Hearing Loss.

The aim of this study is to investigate the efficiency of a first-line molecular genetic evaluation approach, in children with deafness. Patients who were found to have sensorineural hearing loss by age-appropriate audiological tests were selected for the molecular genetic evaluation. The molecular genetic evaluation was carried out with GJB2 gene sequence analysis and mtDNA m.1555A>G mutation Restriction Fragment Length Polymorphism (RFLP) analysis. Additionally, in a small group of patients, hearing loss Multiplex Ligation-dependent Probe Amplification (MLPA) analysis was done out to identify the possible role of copy number changes. In this Turkish cohort, which included 104 index patients and 78 relatives, 33 (31.7%) had Pathogenic/Likely Pathogenic variants. One or more GJB2 sequence variants were identified in 46 (44.1%) of the 104 index patients. The homozygous c.35delG mutation by itself explained the etiology in 24% of our ARSNHL group. In one (5%) of the 20 patients of MLPA group, a hemizygous deletion in POU3F4 gene was detected. In our Turkish cohort, we applied a first-line molecular genetic evaluation approach using GJB2 gene sequence analysis and mtDNA m.1555A>G RFLP analysis. This approach revealed the genetic etiology of 44.1% of our index patients. Additionaly, the results of hearing loss MLPA analysis revealed the limited role of copy number changes in this patient group. Furthermore, with a detailed genotype-phenotype association workup, 2 rare cases of Deafness with Palmoplantar Hyperkeratosis and Keratitis-Ichthyosis-Deafness syndrome were reported.

Genetics of Hearing Loss in North Iran Population: An Update of Spectrum and Frequency of GJB2 Mutations.

Diagnosis of pre-lingual hearing loss (HL) is difficult owing to the high number of genes responsible. The most frequent cause of HL is DFNB1 due to mutations in the GJB2 gene. It represents up to 40% of HL cases in some populations. In Iran, it has previously been shown that DFNB1 accounts for 16-18% of cases but varies among different ethnic groups. Here, we reviewed results from our three previous publications and data from other published mutation reports to provide a comprehensive collection of data for GJB2 mutations and HL in northern Iran. In total, 903 unrelated families from six different provinces, viz., Gilan, Mazandaran, Golestan, Ghazvin, Semnan, and Tehran, were included and analyzed for the type and prevalence of GJB2 mutations. A total of 23 different genetic variants were detected from which 18 GJB2 mutations were identified. GJB2 mutations were 20.7% in the studied northern provinces, which was significantly higher than that reported in southern populations of Iran. Moreover, a gradient in the frequency of GJB2 mutations from north to south Iran was observed. c.35delG was the most common mutation, accounting for 58.4% of the cases studied. This study suggests that c.35delG mutation in GJB2 is the most important cause of HL in northern Iran.