Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families

The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.

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

10.21203/rs.2.19325/v3 ◽

2020 ◽

Author(s):

Yingjie Zhou ◽

Muhammad Tariq ◽

Sijie He ◽

Uzma Abdullah ◽

Jianguo Zhang ◽

...

Keyword(s):

Hearing Loss ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Bioinformatics Analysis ◽

Whole Exome ◽

Causal Genes ◽

Clinical Detection ◽

Syndromic Hearing Loss ◽

Sensory Defect ◽

Pakistani Families

Abstract Background: Hearing loss is the most common sensory defect, and it affects over 6% of the population worldwide. Approximately 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 is 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 from Pakistan with hearing loss and applied WES in selected patients for each pedigree, followed by bioinformatics analysis and Sanger validation to identify the causal genes.Results: Variants in 7 genes were identified and validated in these pedigrees. We identified single candidate variant for 3 pedigrees: GIPC3 (c.937T>C), LOXHD1 (c.6136G>A) and TMPRSS3 (c.941T>C). The remaining 2 pedigrees each contained two candidate variants: TECTA (c.4045G>A) and MYO15A (c.3310G>T and c.9913G>C) for one pedigree and DFNB59 (c.494G>A) and TRIOBP (c.1952C>T) for the other pedigree. The candidate variants 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, and they may indicate the aetiologies of hearing loss in such patients. We also suggest that WES may be a suitable strategy for hearing-loss gene screening in clinical detection.

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Whole exome sequencing identifies novel compound heterozygous pathogenic variants in the MYO15A gene leading to autosomal recessive non-syndromic hearing loss

Molecular Biology Reports ◽

10.1007/s11033-020-05618-w ◽

2020 ◽

Vol 47 (7) ◽

pp. 5355-5364

Author(s):

Akram Sarmadi ◽

Samane Nasrniya ◽

Sina Narrei ◽

Zahra Nouri ◽

Hamidreza Abtahi ◽

...

Keyword(s):

Hearing Loss ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autosomal Recessive ◽

Compound Heterozygous ◽

Pathogenic Variants ◽

Whole Exome ◽

Syndromic 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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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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Molecular diagnosis of non-syndromic hearing loss patients using a stepwise approach

Scientific Reports ◽

10.1038/s41598-021-83493-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jing Wang ◽

Jiale Xiang ◽

Lisha Chen ◽

Hongyu Luo ◽

Xiuhua Xu ◽

...

Keyword(s):

Hearing Loss ◽

Multiplex Pcr ◽

Exome Sequencing ◽

Molecular Diagnosis ◽

Nonsyndromic Hearing Loss ◽

Secondary Findings ◽

Pathogenic Variants ◽

Molecular Etiology ◽

Syndromic Hearing Loss ◽

Generation Sequencing

AbstractHearing loss is one of the most common birth disorders in humans, with an estimated prevalence of 1–3 in every 1000 newborns. This study investigates the molecular etiology of a hearing loss cohort using a stepwise strategy to effectively diagnose patients and address the challenges posed by the genetic heterogeneity and variable mutation spectrum of hearing loss. In order to target known pathogenic variants, multiplex PCR plus next-generation sequencing was applied in the first step; patients which did not receive a diagnosis from this were further referred for exome sequencing. A total of 92 unrelated patients with nonsyndromic hearing loss were enrolled in the study. In total, 64% (59/92) of the patients were molecularly diagnosed, 44 of them in the first step by multiplex PCR plus sequencing. Exome sequencing resulted in eleven diagnoses (23%, 11/48) and four probable diagnoses (8%, 4/48) among the 48 patients who were not diagnosed in the first step. The rate of secondary findings from exome sequencing in our cohort was 3% (2/58). This research presents a molecular diagnosis spectrum of 92 non-syndromic hearing loss patients and demonstrates the benefits of using a stepwise diagnostic approach in the genetic testing of nonsyndromic hearing loss.

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Molecular diagnosis of non-syndromic hearing loss patients using a stepwise approach

10.1101/2020.09.20.20197145 ◽

2020 ◽

Author(s):

Jing Wang ◽

Jiale Xiang ◽

Lisha Chen ◽

Hongyu Luo ◽

Jingjing Xu ◽

...

Keyword(s):

Hearing Loss ◽

Multiplex Pcr ◽

Exome Sequencing ◽

Molecular Diagnosis ◽

Genetic Test ◽

Secondary Findings ◽

Pathogenic Variants ◽

Molecular Etiology ◽

Syndromic Hearing Loss ◽

Generation Sequencing

Background Hearing loss is one of the most common birth disorders in humans with an estimated prevalence of 1-3 in every 1000 newborns. This study has investigated the molecular etiology of a deaf cohort using a stepwise strategy to effectively diagnose patients and the challenges faced to verify genetic heterogenicity and the variable mutation spectrums of hearing loss. Methods In order to target known pathogenic variants, multiplex PCR plus next-generation sequencing was applied in the first tier, while undiagnosed cases were further referred to exome sequencing. A total of 92 unrelated patients with nonsyndromic hearing loss were enrolled. Results In total, 64% (59/92) of patients were molecularly diagnosed, 44 of which were identified in the first tier by multiplex PCR plus sequencing. Of 48 undiagnosed patients from the first tier, exome sequencing identified eleven diagnoses (23%, 11/48) and four probably diagnoses (8%, 4/48). The rate of secondary findings of exome sequencing in our cohort is 3.4%. Conclusion The research presented a molecular diagnosis spectrum of 92 non-syndromic hearing loss patients and demonstrated the benefits of using the stepwise diagnostic approach in the genetic test of the non-syndromic hearing loss patient cohort.

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Putative Digenic GJBI2/MYO7A Inheritance of Hearing Loss Detected in a Patient with 48, XXYY Klinefelter Syndrome

10.21203/rs.3.rs-92862/v1 ◽

2020 ◽

Author(s):

Tian-tian Qin ◽

Qin Zhang ◽

Wen-mu Hu ◽

Muhammad Usman Janjua ◽

Qin Long ◽

...

Keyword(s):

Hearing Loss ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sex Chromosome ◽

Chromosome Abnormality ◽

Klinefelter Syndrome ◽

Compound Heterozygous ◽

Pathogenic Variants ◽

Digenic Inheritance ◽

Whole Exome

Abstract Background: 48, XXYY Klinefelter syndrome is a rare sex chromosome abnormality. Nonsyndromic hearing loss (NSHL) is the most frequent hereditary type of hearing impairment. There has been no report of NSHL combined with 48XXYY. The purpose of this study was to explore the underlying genetic cause in a three-generation family affected by NSHL. The proband had concomitant NSHL and 48, XXYY syndrome. The whole-exome sequencing was performed in the proband. The candidate pathogenic variants identified by whole-exome sequencing were then confirmed by Sanger sequencing and segregation analysis.Results: The proband was identified to be compound heterozygous for c.109G>A (p.V37I) variant in the GJB2 gene and additional heterozygous for the c.1039C>A (p.L347I) variants in the MYO7A gene. His mother had normal hearing and did not have any form of variant. His father and uncle, both had NSHL, were digenic compound heterozygote for the GJB2 p.V37I and MYO7A p.L347I variants, thus suggesting a possible GJB2/MYO7A digenic inheritance of NSHL in this family consist with the clinical phenotype.Conclusions: Our findings reported a putative GJB2/MYO7A digenic inheritance form of hearing loss, which expands the mutation spectrum of NSHL. This is also the first report of concomitant NSHL and 48, XXYY syndrome.

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

BMC Medical Genetics ◽

10.1186/s12881-020-01168-x ◽

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.

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