NGS in Hereditary Ataxia: When Rare Becomes Frequent

The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1, PRKCG, and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.

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Homozygosity mapping and next generation sequencing for the genetic diagnosis of hereditary ataxia and spastic paraplegia in consanguineous families

Parkinsonism & Related Disorders ◽

10.1016/j.parkreldis.2020.09.013 ◽

2020 ◽

Vol 80 ◽

pp. 65-72

Author(s):

Bin Jiao ◽

Zhifan Zhou ◽

Zhengmao Hu ◽

Juan Du ◽

Xinxin Liao ◽

...

Keyword(s):

Next Generation Sequencing ◽

Genetic Diagnosis ◽

Homozygosity Mapping ◽

Next Generation ◽

Spastic Paraplegia ◽

Hereditary Ataxia ◽

Generation Sequencing

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The use of next-generation sequencing in clinical diagnosis of familial hypercholesterolemia

Genetics in Medicine ◽

10.1038/gim.2013.55 ◽

2013 ◽

Vol 15 (12) ◽

pp. 948-957 ◽

Cited By ~ 53

Author(s):

Jana Vandrovcova ◽

Ellen R.A. Thomas ◽

Santosh S Atanur ◽

Penny J. Norsworthy ◽

Clare Neuwirth ◽

...

Keyword(s):

Next Generation Sequencing ◽

Familial Hypercholesterolemia ◽

Molecular Diagnosis ◽

Genetic Diagnosis ◽

Target Enrichment ◽

Next Generation ◽

Large Deletions ◽

Number Of Patients ◽

The Cost ◽

Generation Sequencing

Abstract Purpose: Familial hypercholesterolemia is a common Mendelian disorder associated with early-onset coronary heart disease that can be treated by cholesterol-lowering drugs. The majority of cases in the United Kingdom are currently without a molecular diagnosis, which is partly due to the cost and time associated with standard screening techniques. The main purpose of this study was to test the sensitivity and specificity of two next-generation sequencing protocols for genetic diagnosis of familial hypercholesterolemia. Methods: Libraries were prepared for next-generation sequencing by two target enrichment protocols; one using the SureSelect Target Enrichment System and the other using the PCR-based Access Array platform. Results: In the validation cohort, both protocols showed 100% specificity, whereas the sensitivity for short variant detection was 100% for the SureSelect Target Enrichment and 98% for the Access Array protocol. Large deletions/duplications were only detected using the SureSelect Target Enrichment protocol. In the prospective cohort, the mutation detection rate using the Access Array was highest in patients with clinically definite familial hypercholesterolemia (67%), followed by patients with possible familial hypercholesterolemia (26%). Conclusion: We have shown the potential of target enrichment methods combined with next-generation sequencing for molecular diagnosis of familial hypercholesterolemia. Adopting these assays for patients with suspected familial hypercholesterolemia could improve cost-effectiveness and increase the overall number of patients with a molecular diagnosis. Genet Med 15 12, 948–957.

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Next generation sequencing for molecular diagnosis of neurological disorders using ataxias as a model

Brain ◽

10.1093/brain/awt236 ◽

2013 ◽

Vol 136 (10) ◽

pp. 3106-3118 ◽

Cited By ~ 110

Author(s):

Andrea H. Németh ◽

Alexandra C. Kwasniewska ◽

Stefano Lise ◽

Ricardo Parolin Schnekenberg ◽

Esther B. E. Becker ◽

...

Keyword(s):

Next Generation Sequencing ◽

Molecular Diagnosis ◽

Neurological Disorders ◽

Next Generation ◽

Generation Sequencing

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Next-Generation Sequencing Facilitates Genetic Diagnosis And Improves The Management Of Patients With Hearing Loss In Clinical Practice

10.21203/rs.3.rs-546998/v1 ◽

2021 ◽

Author(s):

Chang Liu ◽

Yanlin Huang ◽

Yan Zhang ◽

Hongke Ding ◽

Lihua Yu ◽

...

Keyword(s):

Hearing Loss ◽

Clinical Practice ◽

Next Generation Sequencing ◽

Diagnostic Yield ◽

Genetic Diagnosis ◽

Study Cohort ◽

Inheritance Pattern ◽

Next Generation ◽

Effective Manner ◽

Generation Sequencing

Abstract Background: Hearing loss (HL) is a prevalent sensorineural disorder, and is among the most etiologically heterogeneous disorders. With the advent of next-generation sequencing (NGS) technologies, hundreds of candidate genes can be analyzed simultaneously in a cost-effective manner. Methods: 94 patients from 87 families diagnosed with non-syndromic or syndromic hearing loss were enrolled. A custom-designed HL panel and clinical exome sequencing (CES) were applied to explore molecular etiology in the cohort, and the efficacy of the two panels was examined. Results: The etiologic diagnosis for hearing loss has been arrived at 40 out of 94 patients (42.6%), 28 with an autosomal recessive (AR) inheritance pattern and 12 with an autosomal dominant (AD) pattern. Candidate variants in 19 different genes were identified in the study cohort, 11 with AR inheritance pattern and 8 with AD pattern. 14 of the variants identified in the study were novel. Compared with CES, the custom-designed HL panel has comparatively higher diagnostic yield (61.5% vs. 29.1%), less expensive price, similar turn-around time, and can be used as an efficient diagnostic tool for hearing loss in the clinical practice. Conclusions: Next-generation sequencing facilitates genetic diagnosis and improves the management of patients with hearing loss in the clinical practice.

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