Comprehensive Genetic Analysis of Japanese Autosomal Dominant Sensorineural Hearing Loss Patients

Iwasa, Yoh-ichiro; Nishio, Shin‐ya; Usami, Shin‐ichi

doi:10.1371/journal.pone.0166781

Cited by 17 publications

(21 citation statements)

References 32 publications

(27 reference statements)

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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: Resultssupporting

confidence: 71%

Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss

et al. 2018

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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 ACMG/AMP guidelines for the interpretation of sequence variants in hearing loss genes. Here, we provide a comprehensive illustration of the newly specified ACMG/AMP hearing loss rules. Three rules remained unchanged, four rules were removed, and the remaining twenty-one rules were specified. These rules were further validated and refined using a pilot set of 51 variants assessed by curators and expert opinion. Of the 51 variants evaluated in the pilot, 37% (19/51) changed category based upon application of the expert panel specified rules and/or aggregation of evidence across laboratories. 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: Resultssupporting

confidence: 71%

Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss

et al. 2018

View full text Add to dashboard Cite

show abstract

“…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: 74%

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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“…The majority of them introduce a premature termination codon, namely c.937dupC (p.Gln313ProfsTer21) [ 25 ], c.1276C>T (p.Arg426Ter) [ 26 ], or c.1609dupC (p.Arg537ProfsTer11) [ 6 ], or result in the deletion of part of exon 5 [ 27 ]. There is only one splicing variant c.1258-1G>A [ 7 ], located in the cryptic 3′ splice site, and two missense variants c.1334A>G (p.Gln445Arg) and c.1547G>A (p.Arg516Gln) [ 25 ] located in the DNA-binding domain or dimerization domain of the protein. GRHL2 is a transcriptional factor [ 5 ] , so those domains are crucial for its function.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, a study that functionally evaluates a larger number of GRHL2 gene variants is required. The clinical presentation of GRHL2-related hearing loss is reported to be moderate, progressive, bilateral, and late-onset [6,7,25,26]. In patients with the splice site GRHL2 variant, the onset was in middle to late adulthood [7], while in patients with the truncating variant c.1609dupC (p.Arg537ProfsTer11), it was variable, with the earliest onset at the age of 7 years [6].…”

Section: Discussionmentioning

confidence: 99%

Novel GRHL2 Gene Variant Associated with Hearing Loss: A Case Report and Review of the Literature

Podkrajšek

Tesovnik

Urbančič

et al. 2021

Genes

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In contrast to the recessive form, hearing loss inherited in a dominant manner is more often post-lingual and typically results in a progressive sensorineural hearing loss with variable severity and late onset. Variants in the GRHL2 gene are an extremely rare cause of dominantly inherited hearing loss. Genetic testing is a crucial part of the identification of the etiology of hearing loss in individual patients, especially when performed with next-generation sequencing, enabling simultaneous analysis of numerous genes, including those rarely associated with hearing loss. We aimed to evaluate the genetic etiology of hearing loss in a family with moderate late-onset hearing loss using next-generation sequencing and to conduct a review of reported variants in the GRHL2 gene. We identified a novel disease-causing variant in the GRHL2 gene (NM_024915: c.1510C>T; p.Arg504Ter) in both affected members of the family. They both presented with moderate late-onset hearing loss with no additional clinical characteristics. Reviewing known GRHL2 variants associated with hearing loss, we can conclude that they are more likely to be truncating variants, while the associated onset of hearing loss is variable.

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Comprehensive Genetic Analysis of Japanese Autosomal Dominant Sensorineural Hearing Loss Patients

Cited by 17 publications

References 32 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

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

Novel GRHL2 Gene Variant Associated with Hearing Loss: A Case Report and Review of the Literature

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