Comprehensive Genetic Analysis of Japanese Autosomal Dominant Sensorineural Hearing Loss Patients

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Abstract

Background

In general, autosomal dominant inherited hearing loss does not have a founder mutation, with the causative mutation different in each family. For this reason, there has been a strong need for efficient diagnosis methods for autosomal dominant sensorineural hearing loss (ADSNHL) patients. This study sought to verify the effectiveness of our analysis algorithm for the screening of ADSNHL patients as well as the usefulness of the massively parallel DNA sequencing (MPS).

Subjects and Methods

Seventy-five Japanese ADSNHL patients from 53 ENT departments nationwide participated in this study. We conducted genetic analysis of 75 ADSNHL patients using the Invader assay, TaqMan genotyping assay and MPS-based genetic screening.

Results

A total of 46 (61.3%) ADSNHL patients were found to have at least one candidate gene variant.

Conclusion

We were able to achieve a high mutation detection rate through the combination of the Invader assay, TaqMan genotyping assay and MPS. MPS could be used to successfully identify mutations in rare deafness genes.

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Most cited references 27

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Forty-six genes causing nonsyndromic hearing impairment: which ones should be analyzed in DNA diagnostics?

Nele Hilgert, Richard Smith, Guy Van Camp (2008)

Hearing impairment is the most common sensory disorder, present in 1 of every 500 newborns. With 46 genes implicated in nonsyndromic hearing loss, it is also an extremely heterogeneous trait. Here, we categorize for the first time all mutations reported in nonsyndromic deafness genes, both worldwide and more specifically in Caucasians. The most frequent genes implicated in autosomal recessive nonsyndromic hearing loss are GJB2, which is responsible for more than half of cases, followed by SLC26A4, MYO15A, OTOF, CDH23 and TMC1. None of the genes associated with autosomal dominant nonsyndromic hearing loss accounts for a preponderance of cases, although mutations are somewhat more frequently reported in WFS1, KCNQ4, COCH and GJB2. Only a minority of these genes is currently included in genetic diagnostics, the selection criteria typically reflecting: (1) high frequency as a cause of deafness (i.e. GJB2); (2) association with another recognisable feature (i.e. SLC26A4 and enlarged vestibular aqueduct); or (3) a recognisable audioprofile (i.e. WFS1). New and powerful DNA sequencing technologies have been developed over the past few years, but have not yet found their way into DNA diagnostics. Implementing these technologies is likely to happen within the next 5 years, and will cause a breakthrough in terms of power and cost efficiency. It will become possible to analyze most - if not all - deafness genes, as opposed to one or a few genes currently. This ability will greatly improve DNA diagnostics, provide epidemiological data on gene-based mutation frequencies, and reveal novel genotype-phenotype correlations.

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Comprehensive genetic testing for hereditary hearing loss using massively parallel sequencing.

Steve Scherer, Michael Hildebrand, A. Eliot Shearer … (2010)

The extreme genetic heterogeneity of nonsyndromic hearing loss (NSHL) makes genetic diagnosis expensive and time consuming using available methods. To assess the feasibility of target-enrichment and massively parallel sequencing technologies to interrogate all exons of all genes implicated in NSHL, we tested nine patients diagnosed with hearing loss. Solid-phase (NimbleGen) or solution-based (SureSelect) sequence capture, followed by 454 or Illumina sequencing, respectively, were compared. Sequencing reads were mapped using GSMAPPER, BFAST, and BOWTIE, and pathogenic variants were identified using a custom-variant calling and annotation pipeline (ASAP) that incorporates publicly available in silico pathogenicity prediction tools (SIFT, BLOSUM, Polyphen2, and Align-GVGD). Samples included one negative control, three positive controls (one biological replicate), and six unknowns (10 samples total), in which we genotyped 605 single nucleotide polymorphisms (SNPs) by Sanger sequencing to measure sensitivity and specificity for SureSelect-Illumina and NimbleGen-454 methods at saturating sequence coverage. Causative mutations were identified in the positive controls but not in the negative control. In five of six idiopathic hearing loss patients we identified the pathogenic mutation. Massively parallel sequencing technologies provide sensitivity, specificity, and reproducibility at levels sufficient to perform genetic diagnosis of hearing loss.

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Genetic etiology study of the non-syndromic deafness in Chinese Hans by targeted next-generation sequencing

Tao-Chieh Yang, Xiaoming Wei, Yongchuan Chai … (2013)

Background Although over 60 non-syndromic deafness genes have been identified to date, the etiologic contribution of most deafness genes remained elusive. In this study, we addressed this issue by targeted next-generation sequencing of a large cohort of non-syndromic deaf probands. Methods Probands with mutations in commonly screened deafness genes GJB2, SLC26A4 and MT-RNR1 were pre-excluded by Sanger sequencing. The remaining 125 deaf probands proceeded through targeted exon capturing of 79 known deafness genes and Illumina HiSeq2000 sequencing. Results Bi-allelic mutations in 15 less commonly screened deafness genes were identified in 28 deaf probands, with mutations in MYO15A, GPR98, TMC1, USH2A and PCDH15 being relatively more frequent (≥3 probands each). Dominant mutations in MYO6, TECTA, POU4F3 and COCH were identified in 4 deaf families. A mitochondrial MTTS1 mutation was identified in one maternally inherited deaf family. No pathogenic mutations were identified in three dominant deaf families and two consanguineous families. Conclusions Mutations in the less commonly screened deafness genes were heterogeneous and contributed to a significant percentage (17.4%) of causes for non-syndromic deafness. Targeted next-generation sequencing provided a comprehensive and efficient diagnosis for known deafness genes. Complementary to linkage analysis or whole-exome sequencing of deaf families, pre-exclusion of known deafness genes by this strategy may facilitate the discovery of novel deafness genes.

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Author and article information

Contributors

Sangdun Choi: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 2 December 2016

Publication date Collection: 2016

Volume: 11

Issue: 12

Electronic Location Identifier: e0166781

Affiliations

[001]Department of Otorhinolaryngology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390–8621, Japan

Ajou University, REPUBLIC OF KOREA

Author notes

Competing Interests: The authors have declared that no competing interests exist.

Conceptualization: SU.
Data curation: SN.
Formal analysis: SN.
Funding acquisition: SU.
Investigation: SN.
Methodology: SN SU.
Project administration: SU.
Resources: SU.
Software: SN.
Supervision: SU.
Validation: YI SN SU.
Visualization: YI SN.
Writing – original draft: YI.
Writing – review & editing: SN SU.

* E-mail: usami@ 123456shinshu-u.ac.jp

Article

Publisher ID: PONE-D-16-18658

DOI: 10.1371/journal.pone.0166781

PMC ID: 5135052

PubMed ID: 27911912

SO-VID: ecf4274b-994a-42bf-960e-4f52e890c444

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 9 May 2016

Date accepted : 3 November 2016

Page count

Figures: 1, Tables: 2, Pages: 11

Funding

This study was grant aided by a Health, Labour and Welfare of Japan Scientific Research Grant (H25-Kankaku-Ippan-002), Japan Agency for Medical Research and Development (15dk0310011h0003), and a Grant-in-Aid for Scientific Research (A) (15H02565) from the Ministry of Education, Science and Culture of Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability Data access is controlled by data access community of the Shinshu University. Data are available from the Shinshu University Institutional Data access / Ethics Committee for researchers who meet the criteria for access to confidential data. If you would like to request access to this data set, please contact Shin-ichi Usami, usami@ 123456shinshu-u.ac.jp .

Comprehensive Genetic Analysis of Japanese Autosomal Dominant Sensorineural Hearing Loss Patients

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Background

Subjects and Methods

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Conclusion

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Most cited references 27

Forty-six genes causing nonsyndromic hearing impairment: which ones should be analyzed in DNA diagnostics?

Comprehensive genetic testing for hereditary hearing loss using massively parallel sequencing.

Genetic etiology study of the non-syndromic deafness in Chinese Hans by targeted next-generation sequencing

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