Dataset Information

Whole exome analysis of patients in Japan with hearing loss reveals high heterogeneity among responsible and novel candidate genes.

ABSTRACT:

Background

Heterogeneous genetic loci contribute to hereditary hearing loss; more than 100 deafness genes have been identified, and the number is increasing. To detect pathogenic variants in multiple deafness genes, in addition to novel candidate genes associated with hearing loss, whole exome sequencing (WES), followed by analysis prioritizing genes categorized in four tiers, were applied.

Results

Trios from families with non-syndromic or syndromic hearing loss (n = 72) were subjected to WES. After segregation analysis and interpretation according to American College of Medical Genetics and Genomics guidelines, candidate pathogenic variants in 11 previously reported deafness genes (STRC, MYO15A, CDH23, PDZD7, PTPN11, SOX10, EYA1, MYO6, OTOF, OTOG, and ZNF335) were identified in 21 families. Discrepancy between pedigree inheritance and genetic inheritance was present in one family. In addition, eight genes (SLC12A2, BAIAP2L2, HKDC1, SVEP1, CACNG1, GTPBP4, PCNX2, and TBC1D8) were screened as single candidate genes in 10 families.

Conclusions

Our findings demonstrate that four-tier assessment of WES data is efficient and can detect novel candidate genes associated with hearing loss, in addition to pathogenic variants of known deafness genes.

SUBMITTER: Mutai H

PROVIDER: S-EPMC8898489 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

Whole exome analysis of patients in Japan with hearing loss reveals high heterogeneity among responsible and novel candidate genes.

Mutai Hideki H Momozawa Yukihide Y Kamatani Yoichiro Y Nakano Atsuko A Sakamoto Hirokazu H Takiguchi Tetsuya T Nara Kiyomitsu K Kubo Michiaki M Matsunaga Tatsuo T

Orphanet journal of rare diseases 20220305 1

<h4>Background</h4>Heterogeneous genetic loci contribute to hereditary hearing loss; more than 100 deafness genes have been identified, and the number is increasing. To detect pathogenic variants in multiple deafness genes, in addition to novel candidate genes associated with hearing loss, whole exome sequencing (WES), followed by analysis prioritizing genes categorized in four tiers, were applied.<h4>Results</h4>Trios from families with non-syndromic or syndromic hearing loss (n = 72) were subj ...[more]

PMID: 35248088

Similar Datasets

Project description:BackgroundDeafness is a highly heterogenous disorder with over 100 genes known to underlie human non-syndromic hearing impairment. However, many more remain undiscovered, particularly those involved in the most common form of deafness: adult-onset progressive hearing loss. Despite several genome-wide association studies of adult hearing status, it remains unclear whether the genetic architecture of this common sensory loss consists of multiple rare variants each with large effect size or many common susceptibility variants each with small to medium effects. As next generation sequencing is now being utilised in clinical diagnosis, our aim was to explore the viability of diagnosing the genetic cause of hearing loss using whole exome sequencing in individual subjects as in a clinical setting.MethodsWe performed exome sequencing of thirty patients selected for distinct phenotypic sub-types from well-characterised cohorts of 1479 people with adult-onset hearing loss.ResultsEvery individual carried predicted pathogenic variants in at least ten deafness-associated genes; similar findings were obtained from an analysis of the 1000 Genomes Project data unselected for hearing status. We have identified putative causal variants in known deafness genes and several novel candidate genes, including NEDD4 and NEFH that were mutated in multiple individuals.ConclusionsThe high frequency of predicted-pathogenic variants detected in known deafness-associated genes was unexpected and has significant implications for current diagnostic sequencing in deafness. Our findings suggest that in a clinic setting, efforts should be made to a) confirm key sequence results by Sanger sequencing, b) assess segregations of variants and phenotypes within the family if at all possible, and c) use caution in applying current pathogenicity prediction algorithms for diagnostic purposes. We conclude that there may be a high number of pathogenic variants affecting hearing in the ageing population, including many in known deafness-associated genes. Our findings of frequent predicted-pathogenic variants in both our hearing-impaired sample and in the larger 1000 Genomes Project sample unselected for auditory function suggests that the reference population for interpreting variants for this very common disorder should be a population of people with good hearing for their age rather than an unselected population.

Dataset Information

Whole exome analysis of patients in Japan with hearing loss reveals high heterogeneity among responsible and novel candidate genes.

Background

Results

Conclusions

Publications

Whole exome analysis of patients in Japan with hearing loss reveals high heterogeneity among responsible and novel candidate genes.

Similar Datasets

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