Targeted sequencing identifies novel variants involved in autosomal recessive hereditary hearing loss in Qatari families

Congenital deafness is one of the most common causes of disability in humans, and more than half of cases are caused by genetic factors. Mutations of the MYO15A gene are the third most common cause of hereditary hearing loss. Using next-generation sequencing combined with auditory tests, two novel compound heterozygous variants c.2802_2812del/c.5681T>C and c.5681T>C/c.6340G>A in the MYO15A gene were identified in probands from two irrelevant Chinese families. Auditory phenotypes of the probands are consistent with the previously reported for recessive variants in the MYO15A gene. The two novel variants, c.2802_2812del and c.5681T>C, were identified as deleterious mutations by bioinformatics analysis. Our findings extend the MYO15A gene mutation spectrum and provide more information for rapid and precise molecular diagnosis of congenital deafness.

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

10.21203/rs.2.19322/v2 ◽

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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Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss

Journal of Translational Medicine ◽

10.1186/s12967-014-0311-1 ◽

2014 ◽

Vol 12 (1) ◽

Cited By ~ 23

Author(s):

Qinjun Wei ◽

Hongmei Zhu ◽

Xuli Qian ◽

Zhibin Chen ◽

Jun Yao ◽

...

Keyword(s):

Hearing Loss ◽

Massively Parallel Sequencing ◽

Massively Parallel ◽

Parallel Sequencing ◽

Hereditary Hearing Loss ◽

Novel Variants

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Characterising the spectrum of autosomal recessive hereditary hearing loss in Iran

Journal of Medical Genetics ◽

10.1136/jmedgenet-2015-103389 ◽

2015 ◽

Vol 52 (12) ◽

pp. 823-829 ◽

Cited By ~ 51

Author(s):

Christina M Sloan-Heggen ◽

Mojgan Babanejad ◽

Maryam Beheshtian ◽

Allen C Simpson ◽

Kevin T Booth ◽

...

Keyword(s):

Hearing Loss ◽

Autosomal Recessive ◽

Hereditary Hearing Loss

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GJB2 mutations causing autosomal recessive non-syndromic hearing loss (ARNSHL) in two Iranian populations: Report of two novel variants

International Journal of Pediatric Otorhinolaryngology ◽

10.1016/j.ijporl.2018.01.012 ◽

2018 ◽

Vol 107 ◽

pp. 121-126 ◽

Cited By ~ 13

Author(s):

Mahbobeh Koohiyan ◽

Morteza Hashemzadeh-Chaleshtori ◽

Mansoor Salehi ◽

Hamidreza Abtahi ◽

Somayeh Reiisi ◽

...

Keyword(s):

Hearing Loss ◽

Autosomal Recessive ◽

Novel Variants ◽

Syndromic Hearing Loss ◽

Gjb2 Mutations ◽

Iranian Populations

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Identification of Novel and Recurrent Variants in MYO15A in Ashkenazi Jewish Patients With Autosomal Recessive Nonsyndromic Hearing Loss

Frontiers in Genetics ◽

10.3389/fgene.2021.737782 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kevin T. Booth ◽

Yoel Hirsch ◽

Anna C. Vardaro ◽

Josef Ekstein ◽

Devorah Yefet ◽

...

Keyword(s):

Hearing Loss ◽

Autosomal Recessive ◽

Null Allele ◽

Mutation Screening ◽

Ashkenazi Jewish ◽

Locus Heterogeneity ◽

Phenotypic Differences ◽

Ashkenazi Jewish Population ◽

Targeted Mutation ◽

Novel Variants

Hearing loss is a genetically and phenotypically heterogeneous disorder. The purpose of this study was to determine the genetic cause underlying hearing loss in four Ashkenazi Jewish families. We screened probands from each family using a combination of targeted mutation screening and exome sequencing to identifiy the genetic cause of hearing loss in each family. We identified four variants in MYO15A, two novel variants never previously linked to deafness (c.7212+5G>A and p.Leu2532ArgfsTer37) and two recurrent variants (p.Tyr2684His and p.Gly3287Gly). One family showed locus heterogeneity, segregrating two genetic forms of hearing loss. Mini-gene assays revealed the c.7212+5G>A variant results in abnormal splicing and is most likely a null allele. We show that families segregrating the p.Gly3287Gly variant show both inter and intra-familial phenotypic differences. These results add to the list of MYO15A deafness-causing variants, further confirm the pathogenicity of the p.Gly3287Gly variant and shed further light on the genetic etiology of hearing loss in the Ashkenazi Jewish population.

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Mutational Spectrum and Clinical Features of Patients with LOXHD1 Variants Identified in an 8074 Hearing Loss Patient Cohort

Genes ◽

10.3390/genes10100735 ◽

2019 ◽

Vol 10 (10) ◽

pp. 735 ◽

Cited By ~ 5

Author(s):

Karuna Maekawa ◽

Shin-ya Nishio ◽

Satoko Abe ◽

Shin-ichi Goto ◽

Yohei Honkura ◽

...

Keyword(s):

Hearing Loss ◽

Clinical Features ◽

Hair Cells ◽

Autosomal Recessive ◽

Haplotype Analysis ◽

Genetic Factors ◽

Hot Spot ◽

Japanese Patients ◽

Novel Variants ◽

Accompanying Symptoms

Variants of the LOXHD1 gene, which are expressed in hair cells of the cochlea and vestibule, have been reported to cause a progressive form of autosomal recessive non-syndromic hereditary hearing loss, DFNB77. In this study, genetic screening was conducted on 8074 Japanese hearing loss patients utilizing massively parallel DNA sequencing to identify individuals with LOXHD1 variants and to assess their phenotypes. A total of 28 affected individuals and 21 LOXHD1 variants were identified, among which 13 were novel variants. A recurrent variant c.4212 + 1G > A, only reported in Japanese patients, was detected in 18 individuals. Haplotype analysis implied that this variation occurred in a mutational hot spot, and that multiple ancestors of Japanese population had this variation. Patients with LOXHD1 variations mostly showed early onset hearing loss and presented different progression rates. We speculated that the varying severities and progression rates of hearing loss are the result of environmental and/or other genetic factors. No accompanying symptoms, including vestibular dysfunction, with hearing loss were detected in this study. Few studies have reported the clinical features of LOXHD1-gene associated hearing loss, and this study is by far the largest study focused on the evaluation of this gene.

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Four Novel Variants in POU4F3 Cause Autosomal Dominant Nonsyndromic Hearing Loss

Neural Plasticity ◽

10.1155/2020/6137083 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Tian-Yi Cui ◽

Xue Gao ◽

Sha-Sha Huang ◽

Yan-Yan Sun ◽

Si-Qi Zhang ◽

...

Keyword(s):

Hearing Loss ◽

Autosomal Dominant ◽

Asian Population ◽

Nonsyndromic Hearing Loss ◽

Hereditary Hearing Loss ◽

Variant Of Uncertain Significance ◽

Targeted Next Generation Sequencing ◽

Pathogenic Variants ◽

Novel Variants ◽

Uncertain Significance

Hereditary hearing loss is one of the most common sensory disabilities worldwide. Mutation of POU domain class 4 transcription factor 3 (POU4F3) is considered the pathogenic cause of autosomal dominant nonsyndromic hearing loss (ADNSHL), designated as autosomal dominant nonsyndromic deafness 15. In this study, four novel variants in POU4F3, c.696G>T (p.Glu232Asp), c.325C>T (p.His109Tyr), c.635T>C (p.Leu212Pro), and c.183delG (p.Ala62Argfs∗22), were identified in four different Chinese families with ADNSHL by targeted next-generation sequencing and Sanger sequencing. Based on the American College of Medical Genetics and Genomics guidelines, c.183delG (p.Ala62Argfs∗22) is classified as a pathogenic variant, c.696G>T (p.Glu232Asp) and c.635T>C (p.Leu212Pro) are classified as likely pathogenic variants, and c.325C>T (p.His109Tyr) is classified as a variant of uncertain significance. Based on previous reports and the results of this study, we speculated that POU4F3 pathogenic variants are significant contributors to ADNSHL in the East Asian population. Therefore, screening of POU4F3 should be a routine examination for the diagnosis of hereditary hearing loss.

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Brief Report of Variants Detected in Hereditary Hearing Loss Cases in Iran over a 3-Year Period

Iranian Journal of Public Health ◽

10.18502/ijph.v48i10.3500 ◽

2020 ◽

Author(s):

Niloofar BAZAZZADEGAN ◽

Raheleh VAZEHAN ◽

Mahsa FADAEE ◽

Zohreh FATTAHI ◽

Ayda ABOLHASSANI ◽

...

Keyword(s):

Hearing Loss ◽

Genetic Testing ◽

Massively Parallel Sequencing ◽

Cost Effective ◽

Massively Parallel ◽

Parallel Sequencing ◽

Hereditary Hearing Loss ◽

Targeted Genomic Enrichment ◽

Novel Variants ◽

Autosomal Recessive Pattern

Background: Diagnosis of hereditary hearing loss (HHL) as a heterogeneous disorder is very important especially in countries with high rates of consanguinity where the autosomal recessive pattern of inheritance is prevalent. Techniques such as next-generation sequencing, a comprehensive genetic test using targeted genomic enrichment and massively parallel sequencing (TGE + MPS), have made the diagnosis more cost-effective. The aim of this study was to determine HHL variants with comprehensive genetic testing in our country. of this study was to determine HHL variants with comprehensive genetic testing in our country. Methods: Fifty GJB2 negative individuals with HHL were referred to the Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, one of the reference diagnostic genetic laboratories in Iran, during a 3-year period between 2014 and 2017. They were screened with the OtoSCOPE test, the targeted genomic enrichment and massively parallel sequencing (TGE + MPS) platform after a detailed history had been taken along with clinical evaluation. Results: Among 32 out of 50 GJB2 negative patients (64%), 34 known pathogenic and novel variants were detected of which 16 (47%) were novel, identified in 10 genes of which the most prevalent were CDH23, MYO7A and MYO15A. Conclusion: These results provide a foundation from which to make appropriate recommendations for the use of comprehensive genetic testing in the evaluation of Iranian patients with hereditary hearing loss.

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