Cases Of Non-syndromic Hearing Loss Research Articles

Targeted Next-Generation Sequencing Analysis Reveals a Novel Genetic Variant in MYO6 Gene in an Indian Family with Postlingual Nonsyndromic Hearing Loss.

Background: Hereditary nonsyndromic hearing loss (NSHL) is an extremely heterogeneous disorder, both genetically and clinically. Myosin VI (MYO6) pathogenic variations have been reported to cause both prelingual and postlingual forms of NSHL. Postlingual autosomal dominant cases are often overlooked for genetic etiology in clinical setups. In this study, we used next-generation sequencing (NGS)-based targeted deafness gene panel assay to identify the cause of postlingual hearing loss in an Indian family. Methods: The proband and his father from a multigenerational Indian family affected by postlingual hearing loss were examined via targeted capture of 129 deafness genes, after excluding gap junction protein beta 2 (GJB2) pathogenic variants by Sanger sequencing. NGS data analysis and co-segregation of the candidate variants in the family were carried out. The variant effect was predicted by in silico tools and interpreted following American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines. Results: A novel heterozygous transversion c.3225T>G, p.(Tyr1075*) in MYO6 gene was identified as the disease-causing variant in this family. This stop-gained variant is predicted to form a truncated myosin VI protein, which is devoid of crucial cargo-binding domain. PCR-RFLP screening in 200 NSHL cases and 200 normal-hearing controls showed the absence of this variant indicating its de novo nature in the population. Furthermore, we reviewed MYO6 variants reported from various populations to date. Conclusions: To the best of our knowledge, this is the first family with MYO6-associated hearing loss from an Indian population. The study also highlights the importance of deafness gene panels in molecular diagnosis of GJB2-negative pedigrees, contributing to genetic counseling in the affected families.

Contiguous Gene Syndromes and Hearing Loss: A Clinical Report of Xq21 Deletion and Comprehensive Literature Review.

Given the crucial role of the personalized management and treatment of hearing loss (HL), etiological investigations are performed early on, and genetic analysis significantly contributes to the determination of most syndromic and nonsyndromic HL cases. Knowing hundreds of syndromic associations with HL, little comprehensive data about HL in genomic disorders due to microdeletion or microduplications of contiguous genes is available. Together with the description of a new patient with a novel 3.7 Mb deletion of the Xq21 critical locus, we propose an unreported literature review about clinical findings in patients and their family members with Xq21 deletion syndrome. We finally propose a comprehensive review of HL in contiguous gene syndromes in order to confirm the role of cytogenomic microarray analysis to investigate the etiology of unexplained HL.

GJB2 c.35del variant up-regulates GJA1 gene expression and affects differentiation of human stem cells.

Pathogenic DNA alterations in GJB2 are present in nearly half of non-syndromic hearing loss cases with autosomal recessive inheritance. The most frequent variant in GJB2 causing non-syndromic hearing loss is the frameshifting c.35del. GJB2 encodes Cx26, a protein of the connexin family that assembles hemichannels and gap junctions. The expression of paralogous proteins is believed to compensate for the loss of function of specific connexins. As Cx26 has been involved in cell differentiation in distinct tissues, we employed stem cells derived from human exfoliated deciduous teeth (SHEDs), homozygous for the c.35del variant, to assess GJB2 roles in stem cell differentiation and the relationship between its loss of function and the expression of paralogous genes. Primary SHED cultures from patients and control individuals were compared. SHEDs from patients had significantly less GJB2 mRNA and increased amount of GJA1 (Cx43), but not GJB6 (Cx30) or GJB3 (Cx31) mRNA. In addition, they presented higher induced differentiation to adipocytes and osteocytes but lower chondrocyte differentiation. Our results suggest that GJA1 increased expression may be involved in functional compensation for GJB2 loss of function in human stem cells, and it may explain changes in differentiation properties observed in SHEDs with and without the c.35del variant.

Novel, pathogenic insertion variant of GSDME associates with autosomal dominant hearing loss in a large Chinese pedigree.

Nonsyndromic hearing loss (NSHL) is a genetically diverse, highly heterogeneous condition characterised by deafness, and Gasdermin E (GSDME) variants have been identified as directly inducing autosomal dominant NSHL. While many NSHL cases associated with GSDME involve the skipping of exon 8, there is another, less understood pathogenic insertion variant specifically found in Chinese pedigrees that causes deafness, known as autosomal dominant 5 (DFNA5) hearing loss. In this study, we recruited a large Chinese pedigree, conducted whole-exome and Sanger sequencing to serve as a comprehensive clinical examination, and extracted genomic DNA samples for co-segregation analysis of the members. Conservation and expression analyses for GSDME were also conducted. Our clinical examinations revealed an autosomal dominant phenotype of hearing loss in the family. Genetic analysis identified a novel insertion variant in GSDME exon 8 (GSDME: NM_004403.3: c.1113_1114insGGGGTGCAGCTTACAGGGTGGGTGT: p. P372fs*36). This variant is segregated with the deafness phenotype of this pedigree. The GSDME gene was highly conserved in the different species we analysed, and its mRNA expression was ubiquitously low in different human tissues. In conclusion, we have successfully identified a novel pathogenic insertion variant of GSDME in a Chinese pedigree that causes deafness, shedding light on the genetic basis of hearing loss within this specific family. Our findings expand the spectrum of known variants associated with GSDME-related deafness and may further support both the underlying gain-of-function mechanism and functional associations of GSDME hearing loss variants.

Spectrum of Genes for Non-GJB2-Related Non-Syndromic Hearing Loss in the Russian Population Revealed by a Targeted Deafness Gene Panel.

Hearing loss is one of the most genetically heterogeneous disorders known. Over 120 genes are reportedly associated with non-syndromic hearing loss (NSHL). To date, in Russia, there have been relatively few studies that apply massive parallel sequencing (MPS) methods to elucidate the genetic factors underlying non-GJB2-related hearing loss cases. The current study is intended to provide an understanding of the mutation spectrum in non-GJB2-related hearing loss in a cohort of Russian sensorineural NSHL patients and establish the best diagnostic algorithm. Genetic testing using an MPS panel, which included 33 NSHL and syndromic hearing loss (SHL) genes that might be misdiagnosed as NSHL genes, was completed on 226 sequentially accrued and unrelated patients. As a result, the molecular basis of deafness was found in 21% of the non-GJB2 NSHL cases. The total contribution pathogenic, and likely pathogenic, variants in the genes studied among all hereditary NSHL Russian patients was 12%. STRC pathogenic and likely pathogenic, variants accounted for 30% of diagnoses in GJB2-negative patients, providing the most common diagnosis. The majority of causative mutations in STRC involved large copy number variants (CNVs) (80%). Among the point mutations, the most common were c.11864G>A (p.Trp3955*) in the USH2A gene, c.2171_2174delTTTG (p.Val724Glyfs*6) in the STRC gene, and c.107A>C (p.His36Pro) and c.1001G>T (p.Gly334Val) in the SLC26A4 gene. Pathogenic variants in genes involved in SHL accounted for almost half of the cases with an established molecular genetic diagnosis, which were 10% of the total cohort of patients with non-GJB2-related hearing loss.

Genetics Landscape of Nonsyndromic Hearing Loss in Indian Populations.

Congenital nonsyndromic hearing loss (NSHL) has been considered as one of the most prevalent chronic disorder in children. It affects the physical and mental conditions of a large children population worldwide. Because of the genetic heterogeneity, the identification of target gene is very challenging. However, gap junction β-2 ( GJB2 ) is taken as the key gene for hearing loss, as its involvement has been reported frequently in NSHL cases. This study aimed to identify the association of GJB2 mutants in different Indian populations based on published studies in Indian population. This will provide clear genetic fundamental of NSHL in Indian biogeography, which would be helpful in the diagnosis process.

Evaluation of GJB2 and GJB6 Mutations in Patients Afflicted with Non-syndromic Hearing Loss

Background Non-syndromic hearing loss (NSHL) is assumed as one of the highly prevalent congenital defects in the world. In this regard, gap junction protein beta 2(GJB2), and gap junction protein beta 6(GJB6) mutations are considered as the leading congenital causes of deafness. The present study aimed to assess the prevalence of GJB2 and GJB6 mutations in NSHL cases. Materials and Methods This cross-sectional study was implemented from Jan. 2015 to Sep. 2017 at Alzahra Hospital (Isfahan, Iran).46 patients afflicted with NSHL were recognized and recruited by physicians. Heparinized blood was collected and DNA of each participant was extracted. Genetic analysis of GJB2 and GJB6 genes was performed using PCR and GAP-PCR methods respectively. Results: 35delG mutation had the highest prevalence with allelic frequency of 6.12%. The allelic frequencies of 35delG, and delE120 were 6(6.12%), and 3(3.06%), respectively. Allelic frequency of W77R, Y65H, G160, and R127H was 2(2.04%) for each of them. In addition, 2 patients were heterozygous for p.V153I rare polymorphism (2.04%). Conclusion Overall, the present study indicated that 35delG mutation could be considered as the foremost causative factor of NHCL. GJB2 mutations were highly prevalent among NSHL cases (23.9%). As a result, the mutation analysis of this gene could be appropriately used for prevention and early diagnosis of NSHL.

New SNP variants of MARVELD2 (DFNB49) associated with non-syndromic hearing loss in Chinese population.

Non-syndromic hearing loss (NSHL) is a common defect in humans. Variants of MARVELD2 at the DFNB49 locus have been shown to cause bilateral, moderate to profound NSHL. However, the role of MARVELD2 in NSHL susceptibility in the Chinese population has not been studied. Here we conducted a case-control study in an eastern Chinese population to profile the spectrum and frequency of MARVELD2 variants, as well as the association of MARVELD2 gene variants with NSHL. Our results showed that variants identified in the Chinese population are significantly different from those reported in Slovak, Hungarian, and Czech Roma, as well as Pakistani families. We identified 11 variants in a cohort of 283 NSHL cases. Through Sanger sequencing and bioinformatics analysis, we found that c.730G>A variant has detrimental effects in the eastern Chinese population, and may have relatively high correlation with NSHL pathogenicity.

Connexin 26 (GJB2) Mutations Associated with Non-Syndromic Hearing Loss (NSHL).

To determine the prevalence and spectrum of Connexin 26 (GJB2) mutations in pre-lingual non-syndromic hearing loss (NSHL) patients in authors' centre and to review the data of Indian patients from the literature. Sanger sequencing of entire coding region contained in single exon (Exon 2) of GJB2 gene in 15 patients of NSHL. GJB2 mutations were found in 40% (6/15) of NSHL patients, out of which mono-allelic were 33.3% (2/6). Bi-allelic GJB2 mutations were identified in 4 of 6 patients. Most common GJB2 mutation identified was c.71G > A(p.W24X), comprising 30% of the total GJB2 mutant alleles. Six studies involving 1119 patients with NSHL were reviewed and 4 of them have reported c.71G > A(p.W24X) as the commonest mutation while 2 studies found c.35delG as the commonest. GJB2 mutations accounted for 10.9%-36% cases of NSHL. Sixteen other mutations in GJB2 gene were reported in Indian patients out of which 6 mutations other than c.71G > A(p.W24X) viz., c.35delG, c.1A > G(p.M1V), c.127G > A(p.V43M), c.204C > G(p.Y86X), c.231G > A(p.W77X) and c.439G > A(p.E147K) were identified in the present study. Connexin 26 (GJB2) mutations are responsible for 19.4% of NSHL in Indian population. The c.71G > A(W24X) and c.35delG were the most prevalent GJB2 mutations accounting for 72.2% (234 of 324 total mutated alleles from 7 studies) and 15.4% (50 of 324 total mutated alleles from 7 studies) respectively. Thus, screening of these two common mutations in GJB2 gene by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) would greatly help in providing easy genetic diagnosis and help in genetic counseling of the families with NSHL.

Functional Testing of SLC26A4 Variants-Clinical and Molecular Analysis of a Cohort with Enlarged Vestibular Aqueduct from Austria.

The prevalence and spectrum of sequence alterations in the SLC26A4 gene, which codes for the anion exchanger pendrin, are population-specific and account for at least 50% of cases of non-syndromic hearing loss associated with an enlarged vestibular aqueduct. A cohort of nineteen patients from Austria with hearing loss and a radiological alteration of the vestibular aqueduct underwent Sanger sequencing of SLC26A4 and GJB2, coding for connexin 26. The pathogenicity of sequence alterations detected was assessed by determining ion transport and molecular features of the corresponding SLC26A4 protein variants. In this group, four uncharacterized sequence alterations within the SLC26A4 coding region were found. Three of these lead to protein variants with abnormal functional and molecular features, while one should be considered with no pathogenic potential. Pathogenic SLC26A4 sequence alterations were only found in 12% of patients. SLC26A4 sequence alterations commonly found in other Caucasian populations were not detected. This survey represents the first study on the prevalence and spectrum of SLC26A4 sequence alterations in an Austrian cohort and further suggests that genetic testing should always be integrated with functional characterization and determination of the molecular features of protein variants in order to unequivocally identify or exclude a causal link between genotype and phenotype.

Mutation Analysis of the Common Deafness Genes in Patients with Nonsyndromic Hearing Loss in Republic of Macedonia

Abstract Hearing impairment is the most common sensory disorder, which occurs in 1 of 1000 newborns. It is caused by heterogeneous conditions with more than a half due to genetic etiology. Although hundreds of genes are implicated in hearing process and have been found to be associated with nonsyndromic hearing loss, pathogenic variants in GJB2 gene have been considered as the main cause of deafness among nonsyndromic hearing loss (NSHL) population worldwide. Pathogenic variants in MT-RNR1 or mtDNA12SrRNA gene were also implicated predominantly in postlingual progresive deafness. The aim of this study was to analyze the implication of GJB2 and MT-RNR1 genes in the molecular etiology of deafness among 130 NSHL patients in the Republic of Macedonia. The presence of the del (GJB6-D13S1830) was also analysed. We performed SSCP and/or sequence analysis of GJB2 and identified sequence variants in 62 out of 130 patients (47.7%); (51 homozygous or compound heterozygous and 11 with only one variant allele). We found 8 different allelic variants, the most prevalent being c.35delG (65.49%), and p.W24*(23.01%), followed by other less frequent alleles (p.V27I, p.V37I, p. P175T and cd. delE120 or delGAG at 360). In addition, two polymorphic substitutions in the GJB2 gene with no clinical significance (p.V153I and p.R127H) were detected. No del(GJB6-D13S1830) was found. SNaPshot analysis was used to screen for the five most frequent allelic variants in the MT-RNR1 gene. Two MT-RNR1 mutations (A827G and T961G) were detected in three patients where only one GJB2 pathogenic variant was found. A new MT-RNR1 gene variant G1303A was also detected. In conclusion, MT-RNR1 mutations were not a significant contributor to the etiology of deafness in Macedonia, although could be considered as a modifier gene affecting the expression of deafness in patients carrying one GJB2 variant. On the other hand, the high percenttage of GJB2 pathogenic variants identified among NSHL cases indicates the necessity of molecular newborn screening for the two most common GJB2 variants (c.35delG and p.W24*) in the Republic of Macedonia.

Application of SNPscan in Genetic Screening for Common Hearing Loss Genes.

The current study reports the successful application of a fast and efficient genetic screening system for common hearing loss (HL) genes based on SNPscan genotyping technology. Genetic analysis of 115 variants in common genes related to HL, GJB2, SLC26A4 and MT-RNR, was performed on 695 subjects with non-syndromic hearing loss (NSHL) from the Northern China. The results found that 38.7% (269/695) of cases carried bi-allelic pathogenic variants in GJB2 and SLC26A4 and 0.7% (5/695) of cases carried homoplasmic MT-RNR1 variants. The variant allele frequency of GJB2, SLC26A4 and MT-RNR1 was 19.8% (275/1390), 21.9% (304/1390), and 0.86% (6/695), respectively. This approach can explain ~40% of NSHL cases and thus is a useful tool for establishing primary molecular diagnosis of NSHL in clinical genetics.

Deafness gene variations in a 1120 nonsyndromic hearing loss cohort: molecular epidemiology and deafness mutation spectrum of patients in Japan.

To elucidate the molecular epidemiology of hearing loss in a large number of Japanese patients analyzed using massively parallel DNA sequencing (MPS) of target genes. We performed MPS of target genes using the Ion PGM system with the Ion AmpliSeq and HiSeq 2000 systems using SureSelect in 1389 samples (1120 nonsyndromic hearing loss cases and 269 normal hearing controls). We filtered the variants identified using allele frequencies in a large number of controls and 12 predication program scores. We identified 8376 kinds of variants in the 1389 samples, and 409 835 total variants were detected. After filtering the variants, we selected 2631 kinds of candidate variants. The number of GJB2 mutations was exceptionally high among these variants, followed by those in CDH23, SLC26A4, MYO15A, COL11A2, MYO7A, and OTOF. We performed a large number of MPS analyses and clarified the genetic background of Japanese patients with hearing loss. This data set will be a powerful tool to discover rare causative gene mutations in highly heterogeneous monogenic diseases and reveal the genetic epidemiology of deafness.

Diagnostic Application of Targeted Resequencing for Familial Nonsyndromic Hearing Loss

Identification of causative genes for hereditary nonsyndromic hearing loss (NSHL) is important to decide treatment modalities and to counsel the patients. Due to the genetic heterogeneity in sensorineural genetic disorders, the high-throughput method can be adapted for the efficient diagnosis. To this end, we designed a new diagnostic pipeline to screen all the reported candidate genes for NSHL. For validation of the diagnostic pipeline, we focused upon familial NSHL cases that are most likely to be genetic, rather than to be infectious or environmental. Among the 32 familial NSHL cases, we were able to make a molecular genetic diagnosis from 12 probands (37.5%) in the first stage by their clinical features, characteristic inheritance pattern and further candidate gene sequencing of GJB2, SLC26A4, POU3F4 or mitochondrial DNA. Next we applied targeted resequencing on 80 NSHL genes in the remaining 20 probands. Each proband carried 4.8 variants that were not synonymous and had the occurring frequency of less than three among the 20 probands. These variants were then filtered out with the inheritance pattern of the family, allele frequency in normal hearing 80 control subjects, clinical features. Finally NSHL-causing candidate mutations were identified in 13(65%) of the 20 probands of multiplex families, bringing the total solve rate (or detection rate) in our familial cases to be 78.1% (25/32) Damaging mutations discovered by the targeted resequencing were distributed in nine genes such as WFS1, COCH, EYA4, MYO6, GJB3, COL11A2, OTOF, STRC and MYO3A, most of which were private. Despite the advent of whole genome and whole exome sequencing, we propose targeted resequencing and filtering strategy as a screening and diagnostic tool at least for familial NSHL to find mutations based upon its efficacy and cost-effectiveness.

Digenic inheritance in autosomal recessive non-syndromic hearing loss cases carrying GJB2 heterozygote mutations: Assessment of GJB4, GJA1, and GJC3

ObjectiveAutosomal recessive non-syndromic hearing loss (ARNSHL) can be caused by many genes. However, mutations in the GJB2 gene, which encodes the gap-junction (GJ) protein connexin (Cx) 26, constitute a considerable proportion differing among population. Between 10 and 42 percent of patients with recessive GJB2 mutations carry only one mutant allele. Mutations in GJB4, GJA1, and GJC3 encoding Cx30.3, Cx43, and Cx29, respectively, can lead to HL. Combination of different connexins in heteromeric and heterotypic GJ assemblies is possible. This study aims to determine whether variations in any of the genes GJB4, GJA1 or GJC3 can be the second mutant allele causing the disease in the digenic mode of inheritance in the studied GJB2 heterozygous cases. MethodsWe examined 34 unrelated GJB2 heterozygous ARNSHL subjects from different geographic and ethnic areas in Iran, using polymerase chain reaction (PCR) followed by direct DNA sequencing to identify any sequence variations in these genes. Restriction fragment length polymorphism (RFLP) assays were performed on 400 normal hearing individuals. ResultsSequence analysis of GJB4 showed five heterozygous variations including c.451C>A, c.219C>T, c.507C>G, c.155_158delTCTG and c.542C>T, with only the latter variation not being detected in any of control samples. There were three heterozygous variations including c.758C>T, c.717G>A and c.3*dupA in GJA1 in four cases. We found no variations in GJC3 gene sequence. ConclusionOur data suggest that GJB4 c.542C>T variant and less likely some variations of GJB4 and GJA1, but not possibly GJC3, can be assigned to ARNSHL in GJB2 heterozygous mutation carriers providing clues of the digenic pattern.

Microarray-based mutation detection of pediatric sporadic nonsyndromic hearing loss in China

Objective To investigate the molecular etiologic causes of sporadic nonsyndromic hearing loss in Chinese children. Methods 179 sporadic nonsyndromic hearing loss children were subjected to microarray-based mutation detection for nine hot spot mutations in four of the most common deafness-related genes, including GJB2, SLC26A4, GJB3, and 12s rRNA. Results The incidence of positive genetic errors was 43.58% with the current set of target genes in sporadic nonsyndromic hearing loss children. Among them, 25.14% of cases had genetic defects in GJB2, 16.76% of cases had pathogenic mutations in SLC26A4, 1.12% of cases were caused by 12s rRNA mutations, and GJB3 mutation was detected in 0.56% of this group of patients. Conclusions Our results demonstrated that genetic factors were important causes for sporadic nonsyndromic hearing loss in Chinese pediatric cases. Mutations of GJB2 and SLC26A4 are two major genetic causes, whereas mutations of GJB3 and 12s rRNA result in the development of hearing loss in a small percentage of sporadic nonsyndromic hearing loss cases. Microarray testing is a helpful and instrumental screening method in the diagnosis of genetic hearing loss.

A Novel Missense Mutation in the Connexin30 Causes Nonsyndromic Hearing Loss

Dysfunctional gap junctions caused by GJB2 (CX26) and GJB6 (CX30) mutations are implicated in nearly half of nonsyndromic hearing loss cases. A recent study identified a heterozygous mutation, c.119C>T (p.A40V), in the GJB6 gene of patients with nonsyndromic hearing loss. However, the functional role of the mutation in hearing loss remains unclear. In this study, analyses of cell biology indicated that a p.A40V missense mutation of CX30 causes CX30 protein accumulation in the Golgi body rather than in the cytoplasmic membrane. The tet-on protein expression system was used for further study of mutant proteins in CX30 and CX30A40V co-expressions and in CX26 and CX30A40V co-expressions. The p.A40V missense mutation exerted a dominant negative effect on both normal CX30 and CX26, which impaired gap junction formation. Moreover, computer-assisted modeling suggested that this p.A40V mutation affects the intra molecular interaction in the hydrophobic core of Trp44, which significantly alters the efficiency of gap junction formation. These findings suggest that the p.A40V mutation in CX30 causes autosomal-dominant nonsyndromic hearing loss. These data provide a novel molecular explanation for the role of GJB6 in hearing loss.

Mutations inGJB2, GJB6and mDNA 1555A>G variant explain only a minority of cases of nonsyndromic hearing loss in the Qatari population

AbstractHereditary hearing loss is a common genetic disorder accounting for at least 60% of prelingual deafness in children. Most cases (70%) are nonsyndromic and are not associated to other signs or symptoms, while the remaining 30% are syndromic. Nonsyndromic hereditary hearing loss has different patterns of inheritance. The most common one is autosomal recessive. This accounts for 75%-85% of the cases. Another 15%-25% of cases are inherited in an autosomal dominant (DNFA) pattern, while the remaining 1%-2% is inherited as X-linked disorder. Several mitochondrial mutations are also reported of which 1555A>G in the 12S rRNA gene is a common cause of mitochondrial-associated deafness in nonsyndromic progressive sensory neural hearing loss and its aminoglycoside induced state.The two major genes for recessive forms are GJB2 and GJB6, which belong to the connexin family. GJB2 and GJB6 code for connexin 26 and connexin 30 proteins, respectively.Here, we report for the first time results of a study in which a...

Prevalence of the GJB2 IVS1+1G >A mutation in Chinese hearing loss patients with monoallelic pathogenic mutation in the coding region of GJB2

BackgroundMutations in the GJB2 gene are the most common cause of nonsyndromic recessive hearing loss in China. In about 6% of Chinese patients with severe to profound sensorineural hearing impairment, only monoallelic GJB2 mutations known to be either recessive or of unclear pathogenicity have been identified. This paper reports the prevalence of the GJB2 IVS1+1G>A mutation in a population of Chinese hearing loss patients with monoallelic pathogenic mutation in the coding region of GJB2.MethodsTwo hundred and twelve patients, screened from 7133 cases of nonsyndromic hearing loss in China, with monoallelic mutation (mainly frameshift and nonsense mutation) in the coding region of GJB2 were examined for the GJB2 IVS1+1G>A mutation and mutations in the promoter region of this gene. Two hundred and sixty-two nonsyndromic hearing loss patients without GJB2 mutation and 105 controls with normal hearing were also tested for the GJB2 IVS1+1G>A mutation by sequencing.ResultsFour patients with monoallelic mutation in the coding region of GJB2 were found carrying the GJB2 IVS1+1G>A mutation on the opposite allele. One patient with the GJB2 c.235delC mutation carried one variant, -3175 C>T, in exon 1 of GJB2. Neither GJB2 IVS1+1G>A mutation nor any variant in exon 1 of GJB2 was found in the 262 nonsyndromic hearing loss patients without GJB2 mutation or in the 105 normal hearing controls.ConclusionTesting for the GJB2 IVS 1+1 G to A mutation explained deafness in 1.89% of Chinese GJB2 monoallelic patients, and it should be included in routine testing of patients with GJB2 monoallelic pathogenic mutation.

Spectrum of GJB2 Mutations in a Cohort of Nonsyndromic Hearing Loss Cases from the Kingdom of Saudi Arabia

Nonsyndromic hearing loss (NSHL) affects a substantial proportion of newborns in the world every year. This proportion increases proportionally with the degree of consanguineous marriages in any society. In the Kingdom of Saudi Arabia, consanguineous marriages are common practice and this is associated with a noticeably high frequency of inherited conditions affecting the resulting progeny, including NSHL. Until now there is no published data on the genetic causes of NSHL in Saudi Arabia, which greatly hindered the ability of local genetic counseling and family planning centers to distinguish between hereditary and nonhereditary forms of NSHL and subsequently could not give information on the possible inheritance of deafness. In addition, the lack of validated genetic tests for NSHL delayed the detection of deafness in affected individuals and may have lowered the efficiency of later medical interventions. Further, the population covered in this study is likely to have a multiethnic background caused by decades of religious and economic migration to this region. To address such problems, we undertook the task of unraveling the genetic causes of hearing loss in Saudi Arabia, starting with identifying the GJB2/DFNB1 mutation spectrum in a cohort of unrelated individuals suffering from mild to profound NSHL. A total of 12 reported GJB2 mutations were identified in 17 out of 109 (15.59%) NSHL cases. Biallelic GJB2 mutations were identified in 11 out of the 109 NSHL cases (10.09%), with c.35delG being the most common (7/11, 63.63%). The remaining six patients were found to have monoallelic GJB2 mutations. Interestingly, biallelic GJB2 mutations were not detected in patients of Arab tribal origins, reflecting the genetic heterogeneity of the western area of the Kingdom of Saudi Arabia. Therefore, ethnically targeted genetic screening for GJB2 mutations could be a useful tool toward the management of NSHL in this area.