Comprehensive Genetic Screening of KCNQ4 in a Large Autosomal Dominant Nonsyndromic Hearing Loss Cohort: Genotype-Phenotype Correlations and a Founder Mutation

Naito, Takehiko; Nishio, Shin‐ya; Iwasa, Yoh-ichiro; Yano, Takuya; Kumakawa, Kozo; Abe, Satoko; Ishikawa, Kotaro; Kojima, Hiromi; Namba, Atsushi; Oshikawa, Chie; Usami, Shin‐ichi

doi:10.1371/journal.pone.0063231

Cited by 53 publications

(53 citation statements)

References 17 publications

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“…20% x 25% = 5%). Our literature search also confirmed a maximum allelic heterogeneity of 5% in any given gene (Hildebrand et al, 2011;Iwasa, Nishio, & Usami, 2016;T. Naito et al, 2013).…”

Section: Dominant Hearing Losssupporting

confidence: 73%

Expert Specification of the ACMG/AMP Variant Interpretation Guidelines for Genetic Hearing Loss

Oza

DiStefano

Hemphill

et al. 2018

Preprint

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(200 WORD LIMIT)Due to the high genetic heterogeneity of hearing loss, current clinical testing includes sequencing large numbers of genes, which often yields a significant number of novel variants.Therefore, the standardization of variant interpretation is crucial to provide consistent and accurate diagnoses. The Hearing Loss Variant Curation Expert Panel was created within the Clinical Genome Resource to provide expert guidance for standardized genomic interpretation in the context of hearing loss. As one of its major tasks, our Expert Panel has adapted the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards and guidelines for the interpretation of sequence variants in hearing loss genes. Here, we provide a comprehensive illustration of the newly specified ACMG/AMP . CC-BY-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/313734 doi: bioRxiv preprint first posted online May. 8, 2018; hearing loss rules. Three rules remained unchanged, four rules were removed, and the remaining twenty-one rules were specified. Of the specified rules, four had general recommendations, seven were gene/disease considerations, seven had strength-level specifications, and three rules had both gene/disease and strength-level specifications. These rules were further validated and refined using a pilot set of 51 variants assessed by curators.These hearing loss-specific ACMG/AMP rules will help standardize variant interpretation, ultimately leading to better care for individuals with hearing loss.

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“…20% x 25% = 5%). Our literature search also confirmed a maximum allelic heterogeneity of 5% in any given gene (Hildebrand et al, 2011;Iwasa, Nishio, & Usami, 2016;T. Naito et al, 2013).…”

Section: Dominant Hearing Losssupporting

confidence: 73%

Expert Specification of the ACMG/AMP Variant Interpretation Guidelines for Genetic Hearing Loss

Oza

DiStefano

Hemphill

et al. 2018

Preprint

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“…Therefore, a total of 6 (8.0%) of the 75 patients were thought to have KCNQ4 mutations. KCNQ4 mutations are considered to be the most important causative mutation in Japanese ADSNHL patients, as we reported previously[18]. WFS1 and COCH gene mutations were also reported to be frequently identified causes of ADSNHL[25, 26].…”

Section: Discussionmentioning

confidence: 63%

“…As a result, we detected causative mutations in 5 patients. KCNQ4 mutations (c.211delC and c.229_230insGC) could not be detected by MPS because of technical limitations (extremely high GC contents), although this mutation was found frequently, as we previously reported[18]. We believe that the 2 nd screening step was particularly useful for detecting KCNQ4 mutations.…”

Section: Discussionmentioning

confidence: 74%

Comprehensive Genetic Analysis of Japanese Autosomal Dominant Sensorineural Hearing Loss Patients

2016

Self Cite

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BackgroundIn 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 MethodsSeventy-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.ResultsA total of 46 (61.3%) ADSNHL patients were found to have at least one candidate gene variant.ConclusionWe 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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“…In their study, 19 families with 7 different mutations were identified in 287 probands from ADNSHL families [6]. Mutations of KCNQ4 were also found in other east Asian region, such as Korea and other Japanese population (Table 1).…”

Section: Discussionmentioning

confidence: 94%

Targeted High-Throughput Sequencing Identifies Pathogenic Mutations in KCNQ4 in Two Large Chinese Families with Autosomal Dominant Hearing Loss

Wang

Zhao

Yi³

et al. 2014

PLoS ONE

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Autosomal dominant non-syndromic hearing loss (ADNSHL) is highly heterogeneous, among them, KCNQ4 is one of the most frequent disease-causing genes. More than twenty KCNQ4 mutations have been reported, but none of them were detected in Chinese mainland families. In this study, we identified a novel KCNQ4 mutation in a five generation Chinese family with 84 members and a known KCNQ4 mutation in a six generation Chinese family with 66 members. Mutation screening of 30 genes for ADNSHL was performed in the probands from thirty large Chinese families with ADNSHL by targeted region capture and high-throughput sequencing. The candidate variants and the co-segregation of the phenotype were verified by polymerase chain reaction (PCR) amplification and Sanger sequencing in all ascertained family members. Then we identified a novel KCNQ4 mutation p.W275R in exon 5 and a known KCNQ4 mutation p.G285S in exon 6 in two large Chinese ADNSHL families segregating with post-lingual high frequency-involved and progressive sensorineural hearing loss. This is the first report of KCNQ4 mutation in Chinese mainland families. KCNQ4, a member of voltage-gated potassium channel family, is likely to be a common gene in Chinese patients with ADNSHL. The results also support that the combination of targeted enrichment and high-throughput sequencing is a valuable molecular diagnostic tool for autosomal dominant hereditary deafness.

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Comprehensive Genetic Screening of KCNQ4 in a Large Autosomal Dominant Nonsyndromic Hearing Loss Cohort: Genotype-Phenotype Correlations and a Founder Mutation

Cited by 53 publications

References 17 publications

Expert Specification of the ACMG/AMP Variant Interpretation Guidelines for Genetic Hearing Loss

Expert Specification of the ACMG/AMP Variant Interpretation Guidelines for Genetic Hearing Loss

Comprehensive Genetic Analysis of Japanese Autosomal Dominant Sensorineural Hearing Loss Patients

Targeted High-Throughput Sequencing Identifies Pathogenic Mutations in KCNQ4 in Two Large Chinese Families with Autosomal Dominant Hearing Loss

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