Genetic Aetiology of Nonsyndromic Hearing Loss in Moravia-Silesia

Background and Objective: Hearing loss is the most common sensory deficit in humans. The aim of this study was to clarify the genetic aetiology of nonsyndromic hearing loss in the Moravian-Silesian population of the Czech Republic. Patients and Methods: This study included 200 patients (93 males, 107 females, mean age 16.9 years, ranging from 4 months to 62 years) with nonsyndromic sensorineural hearing loss. We screened all patients for mutations in GJB2 and the large deletion del(GJB6-D13S1830). We performed further screening for additional genes (SERPINB6, TMIE, COCH, ESPN, ACTG1, KCNQ4, and GJB3) with Sanger sequencing on a subset of patients that were negative for GJB2 mutations. Results: We detected biallelic GJB2 mutations in 44 patients (22%). Among these patients, 63.6%, 9.1% and 2.3% exhibited homozygous c.35delG, p.Trp24*, and p.Met34Thr mutations, respectively. The remaining 25% of these patients exhibited compound heterozygous c.35delG, c.-23+1G>A, p.Trp24*, p.Val37Ile, p.Met34Thr, p.Leu90Pro, c.235delC, c.313_326del14, p.Ser139Asn, and p.Gly147Leu mutations. We found a monoallelic GJB2 mutation in 12 patients (6.6%). We found no pathogenic mutations in the other tested genes. Conclusions: One fifth of our cohort had deafness related to GJB2 mutations. The del(GJB6-D13S1830), SERPINB6, TMIE, COCH, ESPN, ACTG1, GJB3, and KCNQ4 mutations were infrequently associated with deafness in the Moravian-Silesian population. Therefore, we suggest that del(GJB6-D13S1830) testing should be performed only when patients with deafness carry the monoallelic GJB2 mutation.

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Spectrum and Frequency of the GJB2 Gene Mutations Among Latvian Patients with Prelingual Nonsyndromic Hearing Loss

Proceedings of the Latvian Academy of Sciences Section B Natural Exact and Applied Sciences ◽

10.2478/v10046-009-0031-8 ◽

2009 ◽

Vol 63 (4-5) ◽

pp. 198-203

Author(s):

Olga Šterna ◽

Natālija Proņina ◽

Ieva Grīnfelde ◽

Sandra Kušķe ◽

Astrīda Krūmiņa ◽

...

Keyword(s):

Hearing Loss ◽

Gene Mutations ◽

Gjb2 Gene ◽

Connexin 26 ◽

Compound Heterozygous ◽

Nonsyndromic Hearing Loss ◽

Profound Hearing Loss ◽

Common Cause ◽

Gjb2 Mutation ◽

35Delg Mutation

Spectrum and Frequency of the GJB2 Gene Mutations Among Latvian Patients with Prelingual Nonsyndromic Hearing Loss Mutations in the GJB2 gene (connexin 26) are the most common cause of congenital nonsyndromic severe-to-profound hearing loss. Sixty-five hearing impaired probands from Latvia were tested for mutations in the GJB2 gene to determine the percentage of hearing loss attributed to connexin 26 and the types of mutations in this population. A total of 62% of patients tested had GJB2 mutations. Four different mutations in the GJB2 gene were identified in Latvian patients with nonsyndromic sensorineural hearing loss: 35delG, 311-324del14, 235delC and M34T. The most prevalent mutation is 35delG (47% of all probands were homozygous and 8% compound heterozygous). Our findings support the conclusion that the 35delG mutation is the most prevalent GJB2 mutation and that it is the common cause of hereditary nonsyndromic hearing loss in populations of European descent.

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Association of a novel missense mutation in MYO15A with nonsyndromic hearing loss: a case report

10.21203/rs.3.rs-34119/v1 ◽

2020 ◽

Author(s):

Siji Wang ◽

Ziqi Chen ◽

Jiaqiu Dai ◽

Xi Ouyang ◽

Lin Zhu ◽

...

Keyword(s):

Hearing Loss ◽

Missense Mutation ◽

Sanger Sequencing ◽

Three Dimensional ◽

Sensorineural Deafness ◽

Chinese Family ◽

Common Disease ◽

Compound Heterozygous ◽

Nonsyndromic Hearing Loss ◽

Genetic Sequencing

Abstract Background Hearing loss is a common disease globally, and more than 50% of the cases are genetic. Autosomal recessive nonsyndromic hearing loss (ARNSHL) is one of the most common types of hereditary hearing loss. Here, a novel MYO15A missense mutation was identified in a Chinese family with ARNSHL, using targeted genetic sequencing and Sanger sequencing. Case presentation: A 6-year-old girl with congenital nonsyndromic sensorineural deafness was presented from the First Affiliated hospital of Chongqing Medical University, China. We used targeted region sequencing, Sanger sequencing, functional prediction, and three-dimensional protein structure modeling to identify and verify the genes responsible for deafness in the family. Conclusions We found pathogenic compound heterozygous mutations in MYO15A, including a novel missense mutation, c.6353T > C (p.Leu2118Pro). It could provide help not only for genetic counseling but also for further understanding of the functional role of MYO15A mutations.

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High frequency of connexin26 (GJB2) mutations associated with nonsyndromic hearing loss in the population of Kerala, India

International Journal of Pediatric Otorhinolaryngology ◽

10.1016/j.ijporl.2008.11.010 ◽

2009 ◽

Vol 73 (3) ◽

pp. 437-443 ◽

Cited By ~ 19

Author(s):

Anu Yamuna Joseph ◽

T.J. Rasool

Keyword(s):

Hearing Loss ◽

High Frequency ◽

Nonsyndromic Hearing Loss ◽

Gjb2 Mutations

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A novel compound heterozygous mutation of SLC26A4 in two Chinese families with nonsyndromic hearing loss and enlarged vestibular aqueducts

Molecular Medicine Reports ◽

10.3892/mmr.2017.7690 ◽

2017 ◽

Vol 16 (6) ◽

pp. 9011-9016 ◽

Cited By ~ 2

Author(s):

Guang-Jie Zhu ◽

Lu-Sen Shi ◽

Han Zhou ◽

Ye Yang ◽

Jie Chen ◽

...

Keyword(s):

Hearing Loss ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Nonsyndromic Hearing Loss ◽

Chinese Families

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Identification of Novel CDH23 Variants Causing Moderate to Profound Progressive Nonsyndromic Hearing Loss

Genes ◽

10.3390/genes11121474 ◽

2020 ◽

Vol 11 (12) ◽

pp. 1474

Author(s):

Khushnooda Ramzan ◽

Nouf S. Al-Numair ◽

Sarah Al-Ageel ◽

Lina Elbaik ◽

Nadia Sakati ◽

...

Keyword(s):

Hearing Loss ◽

Phenotypic Variability ◽

Usher Syndrome ◽

Three Dimensional ◽

Homozygosity Mapping ◽

Dimensional Structure ◽

Molecular Testing ◽

Compound Heterozygous ◽

Nonsyndromic Hearing Loss ◽

Missense Variants

Mutant alleles of CDH23, a gene that encodes a putative calcium-dependent cell-adhesion glycoprotein with multiple cadherin-like domains, are responsible for both recessive DFNB12 nonsyndromic hearing loss (NSHL) and Usher syndrome 1D (USH1D). The encoded protein cadherin 23 (CDH23) plays a vital role in maintaining normal cochlear and retinal function. The present study’s objective was to elucidate the role of DFNB12 allelic variants of CDH23 in Saudi Arabian patients. Four affected offspring of a consanguineous family with autosomal recessive moderate to profound NSHL without any vestibular or retinal dysfunction were investigated for molecular exploration of genes implicated in hearing impairment. Parallel to this study, we illustrate some possible pitfalls that resulted from unexpected allelic heterogeneity during homozygosity mapping due to identifying a shared homozygous region unrelated to the disease locus. Compound heterozygous missense variants (p.(Asp918Asn); p.(Val1670Asp)) in CDH23 were identified in affected patients by exome sequencing. Both the identified missense variants resulted in a substitution of the conserved residues and evaluation by multiple in silico tools predicted their pathogenicity and variable disruption of CDH23 domains. Three-dimensional structure analysis of human CDH23 confirmed that the residue Asp918 is located at a highly conserved DXD peptide motif and is directly involved in “Ca2+” ion contact. In conclusion, our study identifies pathogenic CDH23 variants responsible for isolated moderate to profound NSHL in Saudi patients and further highlights the associated phenotypic variability with a genotypic hierarchy of CDH23 mutations. The current investigation also supports the application of molecular testing in the clinical diagnosis and genetic counseling of hearing loss.

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Whole exome sequencing identified mutations causing hearing loss in five consanguineous Pakistan families

10.21203/rs.2.19325/v1 ◽

2019 ◽

Author(s):

Yingjie Zhou ◽

Muhammad Tariq ◽

Sijie He ◽

Uzma Abdullah ◽

Jianguo Zhang ◽

...

Keyword(s):

Hearing Loss ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Bioinformatics Analysis ◽

The Other ◽

Whole Exome ◽

Clinical Detection ◽

Syndromic Hearing Loss ◽

Sensory Defect

Abstract Background: Hearing loss is the most common sensory defect that affects over 6% of the population worldwide. About 50%-60% of hearing loss patients are attributed to genetic causes. Currently more than 100 genes have been reported to cause non-syndromic hearing loss. It’s possible and efficient to screen all potential disease-causing genes for hereditary hearing loss by whole exome sequencing (WES).Methods: We collected 5 consanguineous pedigrees with hearing loss from Pakistan and applied WES on selected patients for each pedigree, followed by bioinformatics analysis and Sanger validation to identify the causing genes for them.Results: Variants in 7 genes were identified and validated in these pedigrees. We identified single candidate for 3 pedigrees, which were GIPC3 (c.937T>C), LOXHD1 (c.2935G>A) and TMPRSS3 (c.941T>C). And the remaining 2 pedigrees each contained two candidates, which were TECTA (c.4045G>A) and MYO15A (c.3310G>T and c.1705G>C) for one pedigree and DFNB59 (c.494G>A) and TRIOBP (c.1952C>T) for the other pedigree. The candidates were validated in all available samples by Sanger sequencing.Conclusion: The candidate variants in hearing loss genes were validated to be co-segregated in the pedigrees, which may indicate the reasons for such patients. We also suggested that WES may be suitable strategy for hearing loss gene screening in clinical detection.

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Update of spectrum c.35delG and c.-23+1G>A mutations on theGJB2gene in individuals with autosomal recessive nonsyndromic hearing loss

Annals of Human Genetics ◽

10.1111/ahg.12284 ◽

2018 ◽

Vol 83 (1) ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Fatemeh Azadegan-Dehkordi ◽

Reza Ahmadi ◽

Mahbobeh Koohiyan ◽

Morteza Hashemzadeh-Chaleshtori

Keyword(s):

Hearing Loss ◽

Autosomal Recessive ◽

Nonsyndromic Hearing Loss ◽

C 23

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Whole exome sequencing identified mutations causing hearing loss in five consanguineous Pakistan families

10.21203/rs.2.19325/v2 ◽

2020 ◽

Author(s):

Yingjie Zhou ◽

Muhammad Tariq ◽

Sijie He(Former Corresponding Author) ◽

Uzma Abdullah ◽

Jianguo Zhang(New Corresponding Author) ◽

...

Keyword(s):

Hearing Loss ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Bioinformatics Analysis ◽

The Other ◽

Whole Exome ◽

Clinical Detection ◽

Syndromic Hearing Loss ◽

Sensory Defect

Abstract Background Hearing loss is the most common sensory defect that affects over 6% of the population worldwide. About 50%-60% of hearing loss patients are attributed to genetic causes. Currently more than 100 genes have been reported to cause non-syndromic hearing loss. It’s possible and efficient to screen all potential disease-causing genes for hereditary hearing loss by whole exome sequencing (WES). Methods We collected 5 consanguineous pedigrees with hearing loss from Pakistan and applied WES on selected patients for each pedigree, followed by bioinformatics analysis and Sanger validation to identify the causing genes for them. Results Variants in 7 genes were identified and validated in these pedigrees. We identified single candidate for 3 pedigrees, which were GIPC3 (c.937T>C), LOXHD1 (c.2935G>A) and TMPRSS3 (c.941T>C). And the remaining 2 pedigrees each contained two candidates, which were TECTA (c.4045G>A) and MYO15A (c.3310G>T and c.1705G>C) for one pedigree and DFNB59 (c.494G>A) and TRIOBP (c.1952C>T) for the other pedigree. The candidates were validated in all available samples by Sanger sequencing. Conclusion The candidate variants in hearing loss genes were validated to be co-segregated in the pedigrees, which may indicate the reasons for such patients. We also suggested that WES may be suitable strategy for hearing loss screening in clinical detection.

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

Macedonian Medical Review ◽

10.1515/mmr-2017-0005 ◽

2017 ◽

Vol 71 (1) ◽

pp. 20-26

Author(s):

Emilija Sukarova Stefanovska ◽

Gjorgji Bozhinovski ◽

Ana Momirovska ◽

Marina Davceva Cakar ◽

Elena Sukarova-Angelovska ◽

...

Keyword(s):

Hearing Loss ◽

Modifier Gene ◽

Compound Heterozygous ◽

Nonsyndromic Hearing Loss ◽

Allelic Variants ◽

Republic Of Macedonia ◽

Pathogenic Variants ◽

Molecular Etiology ◽

The Common ◽

The Republic

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.

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