Evaluation of copy number variants for genetic hearing loss: a review of current approaches and recent findings

Abbasi, Wafaa; French, Courtney; Rockowitz, Shira; Kenna, Margaret A.; Shearer, A. Eliot

doi:10.1007/s00439-021-02365-1

Cited by 19 publications

(7 citation statements)

References 82 publications

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“…Although structural variants calling mostly requires whole-exome/genome data, recently, several novel bioinformatic tools have been proposed to detect copy number variation (CNV) using NGS panel data. The CNV calling algorithm can be based on read coverage, paired end, split read and assembly [ 44 ], while most tools that use panel data are based on read coverage [ 45 ]. Because the accuracy of the tools varies depending on the dataset, a combination of these tools is generally suggested for CNV analysis [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

“…Our preliminary results using CODEX2 [ 47 , 48 ], DeCON [ 49 ] and CNV [ 50 ] indicate the promising clinical usage of these tools, as STRC homodeletions were detected among five patients with negative genetic testing results, and all of them had mild-to-moderate hearing loss, which is compatible with the typical phenotypes of STRC mutations. However, owing to the high false-positive rates of these tools, the genetic diagnosis of CNV should be achieved with confirmatory tools, namely multiplex ligation-dependent probe amplification, long-ranged polymerase chain reaction, or long-read sequencing, which enables haplotype phasing [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

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Revisiting Genetic Epidemiology with a Refined Targeted Gene Panel for Hereditary Hearing Impairment in the Taiwanese Population

Lee

Tsai

et al. 2023

Genes

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Hearing impairment is one of the most common sensory disorders in children, and targeted next-generation sequencing (NGS)-based genetic examinations can assist in its prognostication and management. In 2020, we developed a simplified 30-gene NGS panel from the original 214-gene NGS version based on Taiwanese genetic epidemiology data to increase the accessibility of NGS-based examinations. In this study, we evaluated the diagnostic performance of the 30-gene NGS panel and compared it with that of the original 214-gene NGS panel in patient subgroups with different clinical features. Data on the clinical features, genetic etiologies, audiological profiles, and outcomes were collected from 350 patients who underwent NGS-based genetic examinations for idiopathic bilateral sensorineural hearing impairment between 2020 and 2022. The overall diagnostic yield was 52%, with slight differences in genetic etiology between patients with different degrees of hearing impairment and ages of onset. No significant difference was found in the diagnostic yields between the two panels, regardless of clinical features, except for a lower detection rate of the 30-gene panel in the late-onset group. For patients with negative genetic results, where the causative variant is undetectable on current NGS-based methods, part of the negative results may be due to genes not covered by the panel or yet to be identified. In such cases, the hearing prognosis varies and may decline over time, necessitating appropriate follow-up and consultation. In conclusion, genetic etiologies can serve as references for refining targeted NGS panels with satisfactory diagnostic performance.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Revisiting Genetic Epidemiology with a Refined Targeted Gene Panel for Hereditary Hearing Impairment in the Taiwanese Population

Lee

Tsai

et al. 2023

Genes

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“…Our Canadian‐specific findings will continue to inform the development of our NGS panel and highlight new potential genetic therapy targets based on population prevalence. Importantly, our genetic testing included the use of array‐CGH to assess copy number variants, a well‐established method of improving diagnostic yield, decreasing the likelihood that insufficient genetic testing technology was a large contributor to discrepancy in diagnostic rate 20 …”

Section: Discussionmentioning

confidence: 99%

Variants in Genes Associated with Hearing Loss in Children: Prevalence in a Large Canadian Cohort

Wener,

McLennan,

Papsin

et al. 2024

The Laryngoscope

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ObjectiveThe objective of this study was to assess the prevalence of genetic variants associated with hearing loss in a large cohort of children in Canada using high throughput next generation sequencing (NGS).MethodsA total of 485 children with hearing loss underwent NGS testing with an 80 gene panel of syndromic and non‐syndromic variants known to be associated with hearing loss. Genetic variants were classified as pathogenic, likely pathogenic, likely benign, benign, or variants of uncertain significance (VUS), according to the American College of Medical Genetics and Genomics guidelines.ResultsAcross the 80 genes tested, 923 variants, predominantly in 28 genes, were identified in 324 children. Pathogenic variants occurred in 19/80 (23.8%) of the hearing loss related genes tested and confirmed the etiology of hearing loss in 73/485 (15.1%) of children. GJB2 was the most prevalent gene, affecting 28/73 (38.4%) children with confirmed genetic hearing loss in our cohort. Most identified variants (748/923, 81.0%, in 76/80 genes) were of uncertain significance.ConclusionGenetic testing using NGS identified the etiology in approximately 15% of childhood hearing loss in a Canadian cohort which is lower than what is typically reported. GJB2 was the most common genetic cause of hearing loss. VUS are commonly identified, presenting clinical challenges for counseling.Level of EvidenceLevel 4 Laryngoscope, 2024

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“…Copy number variants are a major contributor to hereditary HL, which shows the importance of the inclusion of CNV detection in a molecular diagnostic analysis for HL [ 26 , 27 ]. Although there have been studies that show the importance of CNV analysis of NGS data, in the etiology of deafness, this analysis method is still being optimized for clinical use.…”

Section: Discussionmentioning

confidence: 99%

Genetic screening of a Chinese cohort of children with hearing loss using a next-generation sequencing panel

Lin

et al. 2023

Hum Genomics

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Background At present, the hereditary hearing loss homepage, (https://hereditaryhearingloss.org/), includes 258 deafness genes and more than 500 genes that have been reported to cause deafness. With few exceptions, the region-specific distributions are unclear for many of the identified variants and genes. Methods Here, we used a custom capture panel to perform targeted sequencing of 518 genes in a cohort of 879 deaf Chinese probands who lived in Yunnan. Mutation sites of the parents were performed by high-throughput sequencing and validated by Sanger sequencing. Results The ratio of male to female patients was close to 1:1 (441:438) and the age of onset was mainly under six. Most patients (93.5%) were diagnosed with moderate to severe deafness. Four hundred and twenty-eight patients had variants in a deafness gene, with a detection rate of 48.7%. Pathogenic variants were detected in 98 genes and a number of these were recurrent within the cohort. However, many of the variants were rarely observed in the cohort. In accordance with the American College of Medical Genetics and Genomics, pathogenic, likely pathogenic and variants of uncertain significance accounted for 34.3%, 19.3% and 46.4% of all detected variants, respectively. The most common genes included GJB2, SLC26A4, MYO15A, MYO7A, TMC1, CDH23, USH2A and WFS1, which contained variants in more than ten cases. The two genes with the highest mutation frequency were GJB2 and SLC26A4, which accounted for 28.5% (122/428) of positive patients. We showed that more than 60.3% of coding variants were rare and novel. Of the variants that we detected, 80.0% were in coding regions, 17.9% were in introns and 2.1% were copy number variants. Conclusion The common mutation genes and loci detected in this study were different from those detected in other regions or ethnic groups, which suggested that genetic screening or testing programs for deafness should be formulated in accordance with the genetic characteristics of the region.

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Evaluation of copy number variants for genetic hearing loss: a review of current approaches and recent findings

Cited by 19 publications

References 82 publications

Revisiting Genetic Epidemiology with a Refined Targeted Gene Panel for Hereditary Hearing Impairment in the Taiwanese Population

Revisiting Genetic Epidemiology with a Refined Targeted Gene Panel for Hereditary Hearing Impairment in the Taiwanese Population

Variants in Genes Associated with Hearing Loss in Children: Prevalence in a Large Canadian Cohort

Genetic screening of a Chinese cohort of children with hearing loss using a next-generation sequencing panel

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