Clinical utility and improved speed of analysis by automated variant prioritization system in genetic hearing loss

Abstract Hereditary hearing loss is a monogenic disease with high genetic heterogeneity. Variants in more than 100 deafness genes underlie the basis of its pathogenesis. The aim of this study was to assess the ratio of SNVs in known deafness genes contributing to the etiology of both sporadic and familial sensorineural hearing loss patients from China. DNA samples from 1127 individuals, including normal hearing controls (n = 616), sporadic SNHL patients (n = 433), and deaf individuals (n = 78) from 30 hearing loss pedigrees were collected. The NGS tests included analysis of sequence alterations in 129 genes. The variants were interpreted according to the ACMG/AMP guidelines for genetic hearing loss combined with NGS data from 616 ethnically matched normal hearing adult controls. We identified a positive molecular diagnosis in 226 patients with sporadic SNHL (52.19%) and in patients from 17 deafness pedigrees (56.67%). Ethnically matched MAF filtering reduced the variants of unknown significance by 8.7%, from 6216 to 5675. Some complexities that may restrict causative variant identification are discussed. This report highlight the clinical utility of NGS panels identifying disease-causing variants for the diagnosis of hearing loss and underlines the importance of a broad data of control and ACMG/AMP standards for accurate clinical delineation of VUS variants.

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Powerful use of automated prioritization of candidate variants in genetic hearing loss with extreme etiologic heterogeneity

Scientific Reports ◽

10.1038/s41598-021-99007-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

So Young Kim ◽

Seungmin Lee ◽

Go Hun Seo ◽

Bong Jik Kim ◽

Doo Yi Oh ◽

...

Keyword(s):

Hearing Loss ◽

Molecular Diagnosis ◽

Diagnostic Yield ◽

Molecular Genetic ◽

Genetic Diagnosis ◽

Variant Prioritization ◽

Manual Analysis ◽

Genetic Hearing Loss ◽

Etiologic Heterogeneity ◽

Molecular Genetic Diagnosis

AbstractVariant prioritization of exome sequencing (ES) data for molecular diagnosis of sensorineural hearing loss (SNHL) with extreme etiologic heterogeneity poses a significant challenge. This study used an automated variant prioritization system (“EVIDENCE”) to analyze SNHL patient data and assess its diagnostic accuracy. We performed ES of 263 probands manifesting mild to moderate or higher degrees of SNHL. Candidate variants were classified according to the 2015 American College of Medical Genetics guidelines, and we compared the accuracy, call rates, and efficiency of variant prioritizations performed manually by humans or using EVIDENCE. In our in silico panel, 21 synthetic cases were successfully analyzed by EVIDENCE. In our cohort, the ES diagnostic yield for SNHL by manual analysis was 50.19% (132/263) and 50.95% (134/263) by EVIDENCE. EVIDENCE processed ES data 24-fold faster than humans, and the concordant call rate between humans and EVIDENCE was 97.72% (257/263). Additionally, EVIDENCE outperformed human accuracy, especially at discovering causative variants of rare syndromic deafness, whereas flexible interpretations that required predefined specific genotype–phenotype correlations were possible only by manual prioritization. The automated variant prioritization system remarkably facilitated the molecular diagnosis of hearing loss with high accuracy and efficiency, fostering the popularization of molecular genetic diagnosis of SNHL.

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Emerging Gene Therapies for Genetic Hearing Loss

Journal of the Association for Research in Otolaryngology ◽

10.1007/s10162-017-0634-8 ◽

2017 ◽

Vol 18 (5) ◽

pp. 649-670 ◽

Cited By ~ 40

Author(s):

Hena Ahmed ◽

Olga Shubina-Oleinik ◽

Jeffrey R. Holt

Keyword(s):

Hearing Loss ◽

Gene Therapies ◽

Genetic Hearing Loss

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Genetic hearing loss: a study of 228 Brazilian patients

Genetics and Molecular Biology ◽

10.1590/s1415-47572000000100004 ◽

2000 ◽

Vol 23 (1) ◽

pp. 25-27 ◽

Cited By ~ 3

Author(s):

Silvia Bragagnolo Longhitano ◽

Décio Brunoni

Keyword(s):

Hearing Loss ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

Autosomal Recessive Inheritance ◽

Recessive Inheritance ◽

Dominant Inheritance ◽

Genetic Etiology ◽

Parental Consanguinity ◽

Genetic Hearing Loss ◽

Associated Abnormalities

We studied 228 patients, with suspected or confirmed genetic hearing loss, in order to determine the clinical and genetic diagnoses and etiology of each case. Deafness with no associated abnormalities was found in 146 patients (64%) belonging to 112 families. Syndromic deafness was diagnosed in 82 patients (36%) belonging to 76 families. The genetic etiology was as follows: autosomal recessive inheritance in 40.8% of syndromics and non-syndromics, autosomal dominant inheritance in 13.2% and X-linked recessive in 1.3%. In 44.7% of the cases, the etiology of the hearing loss could not be determined. Monogenic causes are the most possible etiology in the latter cases. Parental consanguinity was found in 22.4% of the cases, and deafness was bilateral, profound and neurosensorial in 47.4% of the patients. An early onset of hearing loss (< 2 years of age) occurred in 46.5% of the cases. These results are similar to previous literature reports.

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VIP-HL: Semi-automated ACMG/AMP variant interpretation platform for genetic hearing loss

10.22541/au.160682407.73344037/v1 ◽

2020 ◽

Author(s):

Jiguang Peng ◽

Jiale Xiang ◽

Xiangqian Jin ◽

Junhua Meng ◽

Nana Song ◽

...

Keyword(s):

Hearing Loss ◽

Expert Panel ◽

Sequence Variant ◽

Variant Interpretation ◽

Web Interface ◽

Online Tool ◽

Genetic Hearing Loss ◽

Genetics And Genomics ◽

Evidence Based Guidelines ◽

User Friendly

The American College of Medical Genetics and Genomics, and the Association for Molecular Pathology (ACMG/AMP) have proposed a set of evidence-based guidelines to support sequence variant interpretation. The ClinGen hearing loss expert panel (HL-EP) introduced further specifications into the ACMG/AMP framework for genetic hearing loss. This study developed a tool named VIP-HL, aiming to semi-automate the HL ACMG/AMP rules. VIP-HL aggregates information from external databases to automate 13 out of 24 ACMG/AMP rules specified by HL-EP, namely PVS1, PS1, PM1, PM2, PM4, PM5, PP3, BA1, BS1, BS2, BP3, BP4, and BP7. We benchmarked VIP-HL using 50 variants where 83 rules were activated by the ClinGen HL-EP. VIP-HL concordantly activated 96% (80/83) rules, significantly higher than that of by InterVar (47%; 39/83). Of 4948 ClinVar star 2+ variants from 142 deafness-related genes, VIP-HL achieved an overall variant interpretation concordance in 88.0% (4353/4948). VIP-HL is an integrated online tool for reliable automated variant classification in hearing loss genes. It assists curators in variant interpretation and provides a platform for users to share classifications with each other. VIP-HL is available with a user-friendly web interface at http://hearing.genetics.bgi.com/.

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