scholarly journals The Cause of Hereditary Hearing Loss in GJB2 Heterozygotes—A Comprehensive Study of the GJB2/DFNB1 Region

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 684
Author(s):  
Dana Safka Brozkova ◽  
Anna Uhrova Meszarosova ◽  
Petra Lassuthova ◽  
Lukáš Varga ◽  
David Staněk ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Causal Variant ◽  
Pathogenic Variant ◽  
Gjb2 Gene ◽  
Diagnostic Problem ◽  
Present Evidence ◽  
Pathogenic Variants ◽  
Number Of Patients ◽  
Sensory Defect ◽  
Comprehensive Study

Hearing loss is a genetically heterogeneous sensory defect, and the frequent causes are biallelic pathogenic variants in the GJB2 gene. However, patients carrying only one heterozygous pathogenic (monoallelic) GJB2 variant represent a long-lasting diagnostic problem. Interestingly, previous results showed that individuals with a heterozygous pathogenic GJB2 variant are two times more prevalent among those with hearing loss compared to normal-hearing individuals. This excess among patients led us to hypothesize that there could be another pathogenic variant in the GJB2 region/DFNB1 locus. A hitherto undiscovered variant could, in part, explain the cause of hearing loss in patients and would mean reclassifying them as patients with GJB2 biallelic pathogenic variants. In order to detect an unknown causal variant, we examined 28 patients using NGS with probes that continuously cover the 0.4 Mb in the DFNB1 region. An additional 49 patients were examined by WES to uncover only carriers. We did not reveal a second pathogenic variant in the DFNB1 region. However, in 19% of the WES-examined patients, the cause of hearing loss was found to be in genes other than the GJB2. We present evidence to show that a substantial number of patients are carriers of the GJB2 pathogenic variant, albeit only by chance.

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 Concurrent genetic and standard screening test for hearing reduction

2020 ◽  
Vol 66 (2) ◽  
pp. 35-40
Author(s):  
Marina Davcheva Chakar ◽  
Gjorgji Bozhinovski ◽  
Emilija Shukarova Stefanovska ◽  
Dejan Trajkov
Keyword(s):  
Hearing Loss ◽  
Hearing Impairment ◽  
Genetic Screening ◽  
Screening Test ◽  
Screening Program ◽  
Deaf Child ◽  
Hearing Screening ◽  
Pathogenic Variant ◽  
Gjb2 Gene ◽  
Brainstem Response

Reduction of hearing is the most common sensory impairment among newborns with an incidence of 1-3 per 1000 births. Introduction of an Auditory Newborn screening program allows early identification of hearing impairment. Mainly, congenital hearing loss in early childhood is a result of genetic changes. Due to high frequency of GJB2 pathogenic variants, its molecular characterization among sensorineural hearing reduction cases is already conducted as a routine analysis in many countries. The aim of this study is to show our initial results in the effort to determine whether genetic screening along with the standard hearing screening in newborns is justified. Otoacoustic emission (OAE) method was conducted in 223 newborns at risk of hearing impairment. Among them, 7 did not pass the test in both ears while 9 exhibited one-sided hearing loss. In all 7 children with indication of profound bilateral deafness, the diagnosis was confirmed using auditory brainstem response. Genetic screening of GJB2 gene was performed in 6 of them. Genetic analysis of GJB2 revealed homozygous state of the most common pathogenic variant 35delG in 3 (50%) of the analyzed infants. In the remaining 3 no pathogenic variant was determined. The results indicate that performing auditory OAE together with genetic screening is justified. In newborns who have not passed the hearing screening test and have profound hearing loss, without other syndrome traits, screening for mutations of GJB2 gene should be conducted. Genetic screening enables establishment of early definite diagnosis for deafness and helps in conducting adequate therapy providing timely rehabilitation and social inclusion of deaf child. Key words: hearing loss, genetic screening, auditory screening, GJB2 gene

scholarly journals The mitochondrial COI/tRNASER(UCN) G7444A mutation may be associated with hearing impairment in a Han Chinese family

2017 ◽  
Vol 20 (2) ◽  
pp. 43-49
Author(s):  
Y Ding ◽  
B-H Xia ◽  
Y-S Teng ◽  
G-C Zhuo ◽  
J-H Leng
Keyword(s):  
Hearing Loss ◽  
Mitochondrial Genome ◽  
Age At Onset ◽  
Han Chinese ◽  
Pathogenic Variant ◽  
Chinese Family ◽  
12S Rrna ◽  
Pathogenic Variants ◽  
Functional Variants ◽  
High Penetrance

Abstract Variations in mitochondrial genome have been found to be associated with hearing loss. Of these, the mitochondrial 12S rRNA and tRNASer(UCN) are the hot-spots for pathogenic variants associated with deafness. To understand the putative role of mitochondrial DNA (mtDNA) variants in hearing loss, we recently screened the variants in mitochondrial genomes in patients with deafness from the Hangzhou area of Zhejiang Province, People’s Republic of China (PRC). In this study, we describe a maternally-inherited Han Chinese family with high penetrance of hearing loss, notably, the penetrance of hearing loss in this family were 80.0 and 40.0%, when the aminoglycoside was included or excluded. Three matrilineal relatives in this pedigree exhibited different levels of hearing loss with different age at onset. In addition, sequence analysis of the complete mitochondrial genome showed the presence of the well-known C1494T pathogenic variant in the 12S rRNA gene and the G7444A pathogenic variant in the COI/ tRNASer(UCN). The C1494T anomaly had been reported to be a pathogenic mutation associated with aminoglycoside-induced and nonsyndromic hearing loss (AINHL), while the G7444A was considered as a secondary mutation associated with deafness. However, the lack of functional variants in GJB2 and TRMU genes suggested that nuclear modified genes may not play important roles in deafness expression. Thus, the combination of G7444A and C1494T pathogenic variants in the mitochondrial genome may account for the high penetrance of hearing loss in this Chinese family.

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 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 Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome

2021 ◽  
Author(s):  
Pauline Arnaud ◽  
Hélène Morel ◽  
Olivier Milleron ◽  
Laurent Gouya ◽  
Christine Francannet ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Somatic Mosaicism ◽  
Variant Calling ◽  
Copy Number Variations ◽  
Pathogenic Variant ◽  
Single Nucleotide Variants ◽  
Bioinformatics Analyses ◽  
Single Nucleotide ◽  
Fbn1 Gene ◽  
Pathogenic Variants

Abstract Purpose Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands. Methods Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene. Results These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations. Conclusion This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.

scholarly journals Quantitative Approach to Fragmented QRS in Arrhythmogenic Cardiomyopathy: From Disease towards Asymptomatic Carriers of Pathogenic Variants

2020 ◽  
Vol 9 (2) ◽  
pp. 545 ◽  
Author(s):  
Rob W. Roudijk ◽  
Laurens P. Bosman ◽  
Jeroen F. van der Heijden ◽  
Jacques M. T. de Bakker ◽  
Richard N. W. Hauer ◽  
...  
Keyword(s):  
Early Stage ◽  
Pathogenic Variant ◽  
Observer Agreement ◽  
Arrhythmogenic Cardiomyopathy ◽  
Fragmented Qrs ◽  
Early Disease Detection ◽  
Pathogenic Variants ◽  
Disease Penetrance ◽  
Ecg Leads ◽  
And Control

Fragmented QRS complexes (fQRS) are common in patients with arrhythmogenic cardiomyopathy (ACM). A new method of fQRS quantification may aid early disease detection in pathogenic variant carriers and assessment of prognosis in patients with early stage ACM. Patients with definite ACM (n = 221, 66%), carriers of a pathogenic ACM-associated variant without a definite ACM diagnosis (n = 57, 17%) and control subjects (n = 58, 17%) were included. Quantitative fQRS (Q-fQRS) was defined as the total amount of deflections in the QRS complex in all 12 electrocardiography (ECG) leads. Q-fQRS was scored by a single observer and reproducibility was determined by three independent observers. Q-fQRS count was feasible with acceptable intra- and inter-observer agreement. Q-fQRS count is significantly higher in patients with definite ACM (54 ± 15) and pathogenic variant carriers (55 ± 10) compared to controls (35 ± 5) (p < 0.001). In patients with ACM, Q-fQRS was not associated with sustained ventricular arrhythmia (p = 0.701) at baseline or during follow-up (p = 0.335). Both definite ACM patients and pathogenic variant carriers not fulfilling ACM diagnosis have a higher Q-fQRS than controls. This may indicate that increased Q-fQRS is an early sign of disease penetrance. In concealed and early stages of ACM the role of Q-fQRS for risk stratification is limited.

scholarly journals Correlation of the Puretone Audiometry Findings with Intraoperative Findings in Patients with Chronic Suppurative Otitis Media

2015 ◽  
Vol 2 (1) ◽  
pp. 4
Author(s):  
Devashri Uday Patil ◽  
Kiran S. Burse ◽  
Shreeya Kulkarni ◽  
Vandana Sancheti ◽  
Chaitanya Bharadwaj
Keyword(s):  
Hearing Loss ◽  
Otitis Media ◽  
Pure Tone ◽  
Pure Tone Audiometry ◽  
Ossicular Chain ◽  
Chronic Suppurative Otitis Media ◽  
Suppurative Otitis Media ◽  
Number Of Patients ◽  
Operative Findings ◽  
Air Conduction

Chronic suppurative otitis media is one of the common otological conditions in India for which patients seek advice from an otorhinolaryngologist. Chronic suppurative otitis media is recurrent and progressive disease which is characterized with tympanic membrane perforation and suppurative discharge. Pure tone audiometry is the most common test used to evaluate auditory sensitivity. Since hearing loss is a common complication of chronic suppurative otitis media, we designed this study to evaluate preoperative pure tone audiometry findings in patients with chronic suppurative otitis media and its correlation with the intra-operative findings. <strong>Aims and Objectives:</strong> 1] To assess the intra-operative findings in patients with chronic suppurative otitis media. 2] To evaluate the correlation between the preoperative pure tone audiometry findings and intra-operative findings in patients with chronic suppurative otitis media. 3] To assess the type of hearing loss and degree of hearing loss in patients with chronic suppurative otitis media. <strong>Materials and Methods:</strong> This is an Observational study carried over a period of 3 years from August 2011 to August 2013. Total number of patients included in this study was 100. <strong>Result:</strong> Out of 100 patients studied 69 % of patients had Tubo-Tympanic type of CSOM, 31 % of patients had Attico-antral type of CSOM. In patients of Safe CSOM; Central perforation was seen in maximum cases 46.4 %, anterior central perforations was seen in 8.7 % cases, posterior central perforations seen in 20.2 % cases, and subtotal perforations seen in 24.63 % cases. In patients of Unsafe CSOM posterosuperior cholesteatoma was seen in maximum cases 67.74 %, and attic cholesteatoma was seen in 32.2 % cases. In safe CSOM patients all ossicles were intact and mobile whereas in unsafe CSOM patients only 4 patients had intact ossicular chain, while maximum patients had ossicular defect. <strong>Conclusion:</strong> Hearing loss depends on size of perforation. Hearing loss increases as the size of perforation increases. Average air conduction threshold and air bone gap did not differ significantly between various groups of ossicular defect. This shows us that neither air conduction nor air bone gap are reliable parameters on basis of which we can predict ossicular status preoperatively.

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