scholarly journals Identification of Main Genetic Causes Responsible for Non-Syndromic Hearing Loss in a Peruvian Population

Genes ◽  
2019 ◽  
Vol 10 (8) ◽  
pp. 581 ◽  
Author(s):  
Figueroa-Ildefonso ◽  
Bademci ◽  
Rajabli ◽  
Cornejo-Olivas ◽  
Villanueva ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Genetic Factors ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Gjb2 Gene ◽  
Pathogenic Variants ◽  
Novel Variants ◽  
Syndromic Hearing Loss ◽  
Different Populations ◽  
Global Population

: Hearing loss (HL) is a common sensory disorder affecting over 5% of the global population. The etiology underlying HL includes congenital and acquired causes; genetic factors are the main cause in over 50% of congenital cases. Pathogenic variants in the GJB2 gene are a major cause of congenital non-syndromic hearing loss (NSHL), while their distribution is highly heterogeneous in different populations. To the best of our knowledge, there is no data regarding the genetic etiologies of HL in Peru. In this study, we screened 133 Peruvian families with NSHL living in Lima. We sequenced both exons of the GJB2 gene for all probands. Seven probands with familial NSHL that remained negative for GJB2 variants underwent whole genome sequencing (WGS). We identified biallelic pathogenic variants in GJB2 in 43 probands; seven were heterozygous for only one allele. The c.427C>T variant was the most common pathogenic variant followed by the c.35delG variant. WGS revealed three novel variants in MYO15A in two probands, one of them was predicted to affect splicing and the others produce a premature stop codon. The Peruvian population showed a complex profile for genetic variants in the GJB2 gene, this particular profile might be a consequence of the admixture history in Peru.

scholarly journals A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 411
Author(s):  
María Lachgar ◽  
Matías Morín ◽  
Manuela Villamar ◽  
Ignacio del Castillo ◽  
Miguel Ángel Moreno-Pelayo
Keyword(s):  
Hearing Loss ◽  
Stop Codon ◽  
Coiled Coil ◽  
Premature Stop Codon ◽  
Scaffolding Protein ◽  
Common Mechanism ◽  
Chinese Family ◽  
Truncating Mutation ◽  
Spanish Family ◽  
Sensory Defect

Nonsyndromic hereditary hearing loss is a common sensory defect in humans that is clinically and genetically highly heterogeneous. So far, 122 genes have been associated with this disorder and 50 of them have been linked to autosomal dominant (DFNA) forms like DFNA68, a rare subtype of hearing impairment caused by disruption of a stereociliary scaffolding protein (HOMER2) that is essential for normal hearing in humans and mice. In this study, we report a novel HOMER2 variant (c.832_836delCCTCA) identified in a Spanish family by using a custom NGS targeted gene panel (OTO-NGS-v2). This frameshift mutation produces a premature stop codon that may lead in the absence of NMD to a shorter variant (p.Pro278Alafs*10) that truncates HOMER2 at the CDC42 binding domain (CBD) of the coiled-coil structure, a region that is essential for protein multimerization and HOMER2-CDC42 interaction. c.832_836delCCTCA mutation is placed close to the previously identified c.840_840dup mutation found in a Chinese family that truncates the protein (p.Met281Hisfs*9) at the CBD. Functional assessment of the Chinese mutant revealed decreased protein stability, reduced ability to multimerize, and altered distribution pattern in transfected cells when compared with wild-type HOMER2. Interestingly, the Spanish and Chinese frameshift mutations might exert a similar effect at the protein level, leading to truncated mutants with the same Ct aberrant protein tail, thus suggesting that they can share a common mechanism of pathogenesis. Indeed, age-matched patients in both families display quite similar hearing loss phenotypes consisting of early-onset, moderate-to-profound progressive hearing loss. In summary, we have identified the third variant in HOMER2, which is the first one identified in the Spanish population, thus contributing to expanding the mutational spectrum of this gene in other populations, and also to clarifying the genotype–phenotype correlations of DFNA68 hearing loss.

scholarly journals Novel MYO15A variants are associated with hearing loss in the two Iranian pedigrees

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Somayeh Khatami ◽  
Masomeh Askari ◽  
Fatemeh Bahreini ◽  
Morteza Hashemzadeh-Chaleshtori ◽  
Saeed Hematian ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Diagnosis ◽  
Clinical Genetic ◽  
Large Size ◽  
Whole Exome ◽  
Novel Variants ◽  
Syndromic Hearing Loss ◽  
Traditional Approaches

Abstract Background Clinical genetic diagnosis of non-syndromic hearing loss (NSHL) is quite challenging. With regard to its high heterogeneity as well as large size of some genes, it is also really difficult to detect causative mutations using traditional approaches. One of the recent technologies called whole-exome sequencing (WES) has been thus developed in this domain to remove the limitations of conventional methods. Methods This study was a report on a research study of two unrelated pedigrees with multiple affected cases of hearing loss (HL). Accordingly, clinical evaluations and genetic analysis were performed in both families. Results The results of WES data analysis to uncover autosomal recessive non-syndromic hearing loss (ARNSHL) disease-causing variants was reported in the present study. Initial analysis identified two novel variants of MYO15A i.e. c.T6442A:p.W2148R and c.10504dupT:p.C3502Lfs*15 correspondingly which were later confirmed by Sanger validations and segregation analyses. According to online prediction tools, both identified variants seemed to have damaging effects. Conclusion In this study, whole exome sequencing were used as a first approach strategy to identify the two novel variants in MYO15A in two Iranian families with ARNSHL.

scholarly journals Whole-Genome Sequencing Improves the Diagnosis of DFNB1 Monoallelic Patients

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1267
Author(s):  
Anaïs Le Nabec ◽  
Mégane Collobert ◽  
Cédric Le Maréchal ◽  
Rémi Marianowski ◽  
Claude Férec ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Gjb2 Gene ◽  
Whole Genome ◽  
Genetic Origin ◽  
Functional Assays ◽  
Syndromic Hearing Loss ◽  
Sensory Defect

Hearing loss is the most common sensory defect, due in most cases to a genetic origin. Variants in the GJB2 gene are responsible for up to 30% of non-syndromic hearing loss. Today, several deafness genotypes remain incomplete, confronting us with a diagnostic deadlock. In this study, whole-genome sequencing (WGS) was performed on 10 DFNB1 patients with incomplete genotypes. New variations on GJB2 were identified for four patients. Functional assays were realized to explore the function of one of them in the GJB2 promoter and confirm its impact on GJB2 expression. Thus, in this study WGS resolved patient genotypes, thus unlocking diagnosis. WGS afforded progress and bridged some gaps in our research.

scholarly journals Mutations in the connexin26/GJB2 gene are the most common event in non-syndromic hearing loss among the German population

2001 ◽  
Vol 17 (6) ◽  
pp. 521-522 ◽  
Author(s):  
Heinz Gabriel ◽  
Petra Kupsch ◽  
J�rgen Sudendey ◽  
Elke Winterhager ◽  
Klaus Jahnke ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Gjb2 Gene ◽  
German Population ◽  
Common Event ◽  
Syndromic Hearing Loss

Association of GJB2 gene mutation with cochlear implant performance in genetic non-syndromic hearing loss

2011 ◽  
Vol 75 (12) ◽  
pp. 1572-1575 ◽  
Author(s):  
Recep Karamert ◽  
Yildirim A. Bayazit ◽  
Senay Altinyay ◽  
Akın Yılmaz ◽  
Adnan Menevse ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Cochlear Implant ◽  
Gene Mutation ◽  
Gjb2 Gene ◽  
Syndromic Hearing Loss

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

2021 ◽  
pp. 98-98
Author(s):  
Bojana Dobric ◽  
Danijela Radivojevic ◽  
Jovana Jecmenica ◽  
Vassos Neocleous ◽  
Pavlos Fanis ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hearing Impairment ◽  
Autosomal Recessive ◽  
Gjb2 Gene ◽  
Compound Heterozygous ◽  
Heterozygous State ◽  
Phenotype Correlation ◽  
Pathogenic Variants ◽  
Environmental Causes ◽  
35Delg Mutation

Introduction/Objective. Hearing impairment (HI) 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 HI 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 PCR-ARMS 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 (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.

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

2021 ◽  
Vol 24 (1) ◽  
pp. 50-61
Author(s):  
Pedram Pouryari Biyachal ◽  
◽  
Najmeh Ranji ◽  
Ali Nazemi ◽  
◽  
...  
Keyword(s):  
Hearing Loss ◽  
Cross Sectional Study ◽  
Gjb2 Gene ◽  
Common Mutation ◽  
Cross Sectional ◽  
Gjb2 Mutation ◽  
Syndromic Hearing Loss ◽  
Pcr Method ◽  
Gilan Province ◽  
35Delg Mutation

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.

scholarly journals Recessive LOXHD1 Variants Cause a Milder Prelingual Hearing Loss: Genotype-Phenotype Correlation and Three Additional Patients With Novel Variants

2020 ◽  
Author(s):  
Sha Yu ◽  
Wen-xia Chen ◽  
Yun-Fei Zhang ◽  
Chao Chen ◽  
Yihua Ni ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Late Onset ◽  
Protein Domain ◽  
Low Frequencies ◽  
Genotype Combination ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Splicing Variants ◽  
Novel Variants ◽  
Children With Hearing Loss

Abstract BackgroundBiallelic mutations in LOXHD1 have been identified as the cause of DFNB77 (deafness, autosomal recessive 77). It is a novel, progressive, severe-profound, and late-onset non-syndromic hearing loss, and is genetically and phenotypically highly heterogeneous. This study aimed to provide an additional three cases of DFNB77 to analyze this complex disease.MethodsWe presented three cases of pediatric patients with prelingual milder form of the DFNB77 with residual hearing at low frequencies. Trio whole-exome sequencing (WES) was conducted to identify the pathogenic variants. Additionally, we reviewed the literature to further analyze the relationships between the genotype and audiology phenotype of LOXHD1 worldwide.ResultsSix novel possible pathogenic LOXHD1 variants in three patients were identified by WES, including three missense, one nonsense, and two splicing variants. The literature review showed that 68.5% of DFNB77 patient onset before five years old; Most variants (60%) were associated with a milder phenotype, particularly variants in the protein domain of PLAT 7 and PLAT 9. We found that compared with homozygous LOXHD1 variants, individuals with heterozygous compound variants had a significantly milder phenotype, especially individuals carrying one missense and one splicing or bi-allelic missense variants (P <0.05). Audiometric analysis at different ages showed that the hearing loss degree was aggravated at all frequencies in adulthood and more severe in elderhood.ConclusionsWe report three children with hearing loss carrying six novel LOXHD1 variants identified by WES. Furthermore, our work indicates that DFNB77 may be milder than previously reported, and recommends considering the genotype combination and mutation location of LOXHD1 and race-specificity in DFNB77 molecular diagnoses and management.

scholarly journals Novel MYO15A Variants are Associated with Hearing Loss in the Two Iranian Pedigrees

2020 ◽  
Author(s):  
somayeh khatami ◽  
Masomeh Askari ◽  
Fatemeh Bahreini ◽  
Morteza Hashemzadeh Chaleshtori ◽  
Saeed Hematian ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Recessive ◽  
Genetic Diagnosis ◽  
Clinical Genetic ◽  
Clinical Evaluations ◽  
Large Size ◽  
Whole Exome ◽  
Novel Variants ◽  
Syndromic Hearing Loss ◽  
Traditional Approaches

Abstract Background: Clinical genetic diagnosis of non-syndromic hearing loss (NSHL) is quite challenging. With regard to its high heterogeneity as well as large size of some genes, it is also really difficult to detect causative mutations using traditional approaches. One of the recent technologies called whole-exome sequencing (WES) has been thus developed in this domain to remove the limitations of conventional methods.Methods: This study was a report on two unrelated pedigrees with multiple affected cases of hearing loss (HL). Accordingly, clinical evaluations and genetic analysis were performed in both families. Results: The implementation of WES to uncover autosomal recessive non-syndromic hearing loss (ARNSHL) and its related variants was reported in the present study. Two novel variants of MYO15A i.e. c.T6442A:p.W2148R and c.10504dupT:p.C3502Lfs*15 were correspondingly identified and then segregations were confirmed using Sanger sequencing. According to online prediction tools, both identified variants seemed to have damaging effects.Conclusion: This study further supported the effectiveness of WES for genetic diagnosis of ARNSHL as a first approach.

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