Targeted Next-Generation Sequencing Successfully Detects Causative Genes in Chinese Patients with Hereditary Hearing Loss

Chen, Siqi; Dong, Chen; Wang, Qi; Zhong, Zhengrong; Qi, Yu; Ke, Xiaomei; Liu, Yuhe

doi:10.1089/gtmb.2016.0051

Cited by 32 publications

(20 citation statements)

References 22 publications

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“…Residue p.T1237, which forms a hydrogen bond with p.E1172 at this interface, is associated to inherited deafness. The mutation p.T1237P is correlated with a deafness phenotype, although causality has not been established (100). Interestingly, the ring-like arrangement (Fig.…”

Section: Pig Pcdh15 Ec10-mad12 Forms Parallel Cis Dimers In Crystallomentioning

confidence: 99%

A Mechanically Weak Extracellular Membrane-Adjacent Domain Induces Dimerization of Protocadherin-15

De-la-Torre

Choudhary

Araya-Secchi

et al. 2018

Biophysical Journal

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Section: Pig Pcdh15 Ec10-mad12 Forms Parallel Cis Dimers In Crystallomentioning

confidence: 99%

A Mechanically Weak Extracellular Membrane-Adjacent Domain Induces Dimerization of Protocadherin-15

De-la-Torre

Choudhary

Araya-Secchi

et al. 2018

Biophysical Journal

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“…Since single gene tests and multi-gene panels tend to be the first step in genetic diagnosis of specific clinical diseases. The validity and utility of NGS-based panel testing has been demonstrated for a wide range of conditions including: hearing loss, vision loss, cardiovascular disorders, renal disorders, neurologic disorders, and cancer predispositions [[3], [4], [5],9,16].…”

Section: Introductionmentioning

confidence: 99%

Next generation sequencing for clinical diagnostics: Five year experience of an academic laboratory

Hartman

Beckman

Silverstein

et al. 2019

Molecular Genetics and Metabolism Reports

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Clinical laboratories have adopted next generation sequencing (NGS) as a gold standard for the diagnosis of hereditary disorders because of its analytic accuracy, high throughput, and potential for cost-effectiveness. We describe the implementation of a single broad-based NGS sequencing assay to meet the genetic testing needs at the University of Minnesota. A single hybrid capture library preparation was used for each test ordered, data was informatically blinded to clinically-ordered genes, and identified variants were reviewed and classified by genetic counselors and molecular pathologists. We performed 2509 sequencing tests from August 2012 till December 2017. The diagnostic yield has remained steady at 25%, but the number of variants of uncertain significance (VUS) included in a patient report decreased over time with 50% of the patient reports including at least one VUS in 2012 and only 22% of the patient reports reporting a VUS in 2017 (p = .002). Among the various clinical specialties, the diagnostic yield was highest in dermatology (60% diagnostic yield) and ophthalmology (42% diagnostic yield) while the diagnostic yield was lowest in gastrointestinal diseases and pulmonary diseases (10% detection yield in both specialties). Deletion/duplication analysis was also implemented in a subset of panels ordered, with 9% of samples having a diagnostic finding using the deletion/duplication analysis. We have demonstrated the feasibility of this broad-based NGS platform to meet the needs of our academic institution by aggregating a sufficient sample volume from many individually rare tests and providing a flexible ordering for custom, patient-specific panels.

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“…Among these, only 1 patient carried two types of CNVs, while the remaining 10 had only one heterozygous form of CNV without any other form of variation in the COL11A2 gene. Chen et al[24] detected p.Pro445Ser in 116 Chinese patients with hereditary hearing loss using next-generation sequencing that examined 60 genes relevant to hearing loss. Thus, COL11A2 gene is not the main cause of deafness and could be easily missed by the conventional sequencing approach.…”

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confidence: 99%

Whole exome sequencing of six Chinese families with hereditary non-syndromic hearing loss

Liang

Chen

Wang

et al. 2021

International Journal of Pediatric Otorhinolaryngology

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Background:Hereditary non-syndromic hearing loss (NSHL) has a high genetic heterogeneity with >152 genes identi ed as associated molecular causes. The present study aimed to detect the possible damaging variants of the deaf probands from six unrelated Chinese families. Methods:After excluding the mutations in the most common genes, GJB2 and SLC26A4, 12 probands with prelingual deafness and autosomal recessive inheritance were evaluated by whole-exome sequencing (WES). All the candidate variants were veri ed by Sanger sequencing in all patients and their parents. Results:Biallelic mutations were identi ed in all deaf patients. Among these six families, 10 potentially causative mutations, including 3 reported and 7 novel mutations, in 3 different deafness-associated autosomal recessive (DFNB) genes (MYO15A, COL11A2, and CDH23) were identi ed. The mutations in MYO15A were frequent with 7/10 candidate variants. Sanger sequencing con rmed that these mutations segregated with the hearing loss of each family. Conclusions:Next-generation sequencing (NGS) approach becomes more cost-effective and e cient when analyzing large-scale genes compared to the conventional polymerase chain reaction-based Sanger sequencing, which is often used to screen common deafness-related genes. The current ndings further extend the mutation spectrum of hearing loss in the Chinese population, which has a positive signi cance for genetic counseling. gene (14.5%) are the second common pathogenic cause of DFNB in addition to the GJB2 gene (17.9%) [8,9]. Sanger sequencing to detect mutations in GJB2 and SLC26A4 is a routine method during genetic testing and counseling for deafness patients. However, for GJB2 or SLC26A4-negative patients, especially those from small-sized recessive families, the potential genetic causes for deafness are yet unclear.The genetic heterogeneity of hearing loss, with about 152 deafness-associated genes, identi ed to be associated with NSHL [10], makes conventional polymerase chain reaction (PCR)-based Sanger sequencing impractical for large-scale gene detection because of its cost-ine ciency and timeconsumption [11]. In recent years, next-generation sequencing (NGS) approach may make it possible to analyze multiple genes, including all the deafness-associated genes, in one test [12]. Whole exome sequencing (WES), a platform of NGS, offers powerful applications for diagnosis as well as identifying rare variants or new causative genes [13,14].In this study, we utilized WES to investigate the contributing genetic factors in patients from six unrelated Chinese families with autosomal recessive hearing loss but did not harbor GJB2 and SLC26A4 mutations. MethodsSix unrelated Chinese families (code as HL01-06) were recruited from the outpatient clinic of the

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Targeted Next-Generation Sequencing Successfully Detects Causative Genes in Chinese Patients with Hereditary Hearing Loss

Abstract: NGS can be used effectively to identify both the common and rare genes causing hereditary hearing loss.

Cited by 32 publications

References 22 publications

A Mechanically Weak Extracellular Membrane-Adjacent Domain Induces Dimerization of Protocadherin-15

A Mechanically Weak Extracellular Membrane-Adjacent Domain Induces Dimerization of Protocadherin-15

Next generation sequencing for clinical diagnostics: Five year experience of an academic laboratory

Whole exome sequencing of six Chinese families with hereditary non-syndromic hearing loss

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