Improving hearing loss gene testing: a systematic review of gene evidence toward more efficient next-generation sequencing–based diagnostic testing and interpretation

Tayoun, Ahmad Abou; Turki, Saeed Al; Oza, Andrea M.; Bowser, Mark J.; Hernandez, Amy Lovelette; Funke, Birgit; Rehm, Heidi L.; Amr, Sami S.

doi:10.1038/gim.2015.141

Cited by 65 publications

(64 citation statements)

References 45 publications

(27 reference statements)

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“…The 72 known NSHL-associated genes were first examined for the presence of variants (Table S3)25. Whole exome sequencing of these genes achieved an average coverage of 65.8 (Table S4).…”

Section: Resultsmentioning

confidence: 99%

“…As shown in Table S4, WES fails to capture certain regions of the exome, which vary depending on the exome capture kit used. In addition, there are mitochondrial genes and microRNAs associated with NSHL25 and these are not generally covered by WES. Therefore, WES users need to know the type of capture kit used and consider and resolve any uncovered regions.…”

Section: Discussionmentioning

confidence: 99%

“…In step 3, synonymous variants and intronic variants not located within splice site regions were excluded. In step 4, variants of all 72 genes known to be monogenic factors for NSHL were systematically evaluated25. In step 5, if there were no possible causative variant, a recessive inheritance pattern was assumed on the basis of the pedigree analysis results.…”

Section: Methodsmentioning

confidence: 99%

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Genetic Predisposition to Sporadic Congenital Hearing Loss in a Pediatric Population

Jung

Lee

Cho

et al. 2017

Sci Rep

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Discriminating between inherited and non-inherited sporadic hearing loss is challenging. Here, we attempted to delineate genetic inheritance in simplex cases of severe-to-profound congenital hearing loss in Korean children. Variations in SLC26A4 and GJB2 in 28 children with bilateral severe-to-profound non-syndromic hearing loss (NSHL) without familial history were analyzed using Sanger sequencing. Genetic analysis of individuals without mutations in SLC26A4 and GJB2 was performed by whole exome sequencing (WES). Bi-allelic mutations in SLC26A4 and GJB2 were identified in 12 and 3 subjects, respectively. Of the 13 individuals without mutations in SLC26A4 and GJB2, 2 and 1 carried compound heterozygous mutations in MYO15A and CDH23, respectively. Thus, 64.3% (18/28) of individuals with NSHL were determined to be genetically predisposed. Individuals with sporadic severe-to-profound NSHL were found to mostly exhibit an autosomal recessive inheritance pattern. Novel causative candidate genes for NSHL were identified by analysis of WES data of 10 families without mutations in known causative genes. Bi-allelic mutations predisposing to NSHL were identified in 64.3% of subjects with sporadic severe-to-profound NSHL. Given that several causative genes for NSHL are still unidentified, genetic inheritance of sporadic congenital hearing loss could be more common than that indicated by our results.

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“…The 72 known NSHL-associated genes were first examined for the presence of variants (Table S3)25. Whole exome sequencing of these genes achieved an average coverage of 65.8 (Table S4).…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Genetic Predisposition to Sporadic Congenital Hearing Loss in a Pediatric Population

Jung

Lee

Cho

et al. 2017

Sci Rep

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“…It has been hypothesized that EVA may result from digenic inheritance of one recessive SLC26A4 mutation and a second recessive mutation in another gene (Yang et al , , ), but the evidence is not conclusive (Choi et al , ). Variants of KCNJ10 and FOXI1 have been associated with EVA although support for the involvement of these genes is not robust (Yang et al , , ; Abou Tayoun et al , ) and has not been reproducible.…”

Section: Pendred Syndrome Enlarged Vestibular Aqueduct and The Mystmentioning

confidence: 99%

Unresolved questions regarding human hereditary deafness

Rehman

Griffith

2016

Oral Diseases

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Human hearing loss is a common neurosensory disorder about which many basic research and clinically relevant questions are unresolved. This review on hereditary deafness focuses on three examples considered at first glance to be uncomplicated, however, upon inspection, are enigmatic and ripe for future research efforts. The three examples of clinical and genetic complexities are drawn from studies of (1) Pendred syndrome/DFNB4 (PDS, OMIM 274600), (2) Perrault syndrome (deafness and infertility) due to mutations of CLPP (PRTLS3, OMIM 614129), and (3) the unexplained extensive clinical variability associated with TBC1D24 mutations. At present, it is unknown how different mutations of TBC1D24 cause nonsyndromic deafness (DFNB86, OMIM 614617), epilepsy (OMIM 605021), epilepsy with deafness, or DOORS syndrome (OMIM 220500) that is characterized by deafness, onychodystrophy (alteration of toenail or fingernail morphology), osteodystrophy (defective development of bone), intellectual disability and seizures. A comprehensive understanding of the multifaceted roles of each gene associated with human deafness is expected to provide future opportunities for restoration as well as preservation of normal hearing.

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“…Uncertainty at the variant, gene, and less so at the phenotype levels can lead to a VUS call. In the absence of the appropriate standards, wrong assertions about variant and gene causality have been made in the literature and current databases [90; 91]. This is a serious hindrance to effective data sharing.…”

Section: Interpretation Challengesmentioning

confidence: 99%

Sequencing-based diagnostics for pediatric genetic diseases: progress and potential

Krock

2016

Expert Review of Molecular Diagnostics

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Introduction The last two decades have witnessed revolutionary changes in clinical diagnostics, fueled by the Human Genome Project and advances in high throughput, Next Generation Sequencing (NGS). We review the current state of sequencing-based pediatric diagnostics, associated challenges, and future prospects. Areas Covered We present an overview of genetic disease in children, review the technical aspects of Next Generation Sequencing and the strategies to make molecular diagnoses for children with genetic disease. We discuss the challenges of genomic sequencing including incomplete current knowledge of variants, lack of data about certain genomic regions, mosaicism, and the presence of regions with high homology. Expert Commentary NGS has been a transformative technology and the gap between the research and clinical communities has never been so narrow. Therapeutic interventions are emerging based on genomic findings and the applications of NGS are progressing to prenatal genetics, epigenomics and transcriptomics.

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Improving hearing loss gene testing: a systematic review of gene evidence toward more efficient next-generation sequencing–based diagnostic testing and interpretation

Cited by 65 publications

References 45 publications

Genetic Predisposition to Sporadic Congenital Hearing Loss in a Pediatric Population

Genetic Predisposition to Sporadic Congenital Hearing Loss in a Pediatric Population

Unresolved questions regarding human hereditary deafness

Sequencing-based diagnostics for pediatric genetic diseases: progress and potential

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