A Targeted Gene Panel That Covers Coding, Non-coding and Short Tandem Repeat Regions Improves the Diagnosis of Patients With Neurodegenerative Diseases
Genetic testing for neurodegenerative diseases (NDs) is highly challenging because of genetic heterogeneity and overlapping manifestations. Targeted-gene panels (TGPs), coupled with next-generation sequencing (NGS), can facilitate the profiling of a large repertoire of ND-related genes. Due to the t...
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| Format: | Article |
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Frontiers Media S.A.
2019-12-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2019.01324/full |
| _version_ | 1818561819338342400 |
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| author | Allen Chi-Shing Yu Allen Chi-Shing Yu Aldrin Kay-Yuen Yim Aldrin Kay-Yuen Yim Anne Yin-Yan Chan Liz Y. P. Yuen Wing Chi Au Wing Chi Au Timothy H. T. Cheng Xiao Lin Jing-Woei Li Larry W. L. Chan Vincent C. T. Mok Vincent C. T. Mok Ting-Fung Chan Ting-Fung Chan Ting-Fung Chan Ho Yin Edwin Chan Ho Yin Edwin Chan Ho Yin Edwin Chan |
| author_facet | Allen Chi-Shing Yu Allen Chi-Shing Yu Aldrin Kay-Yuen Yim Aldrin Kay-Yuen Yim Anne Yin-Yan Chan Liz Y. P. Yuen Wing Chi Au Wing Chi Au Timothy H. T. Cheng Xiao Lin Jing-Woei Li Larry W. L. Chan Vincent C. T. Mok Vincent C. T. Mok Ting-Fung Chan Ting-Fung Chan Ting-Fung Chan Ho Yin Edwin Chan Ho Yin Edwin Chan Ho Yin Edwin Chan |
| author_sort | Allen Chi-Shing Yu |
| collection | DOAJ |
| description | Genetic testing for neurodegenerative diseases (NDs) is highly challenging because of genetic heterogeneity and overlapping manifestations. Targeted-gene panels (TGPs), coupled with next-generation sequencing (NGS), can facilitate the profiling of a large repertoire of ND-related genes. Due to the technical limitations inherent in NGS and TGPs, short tandem repeat (STR) variations are often ignored. However, STR expansions are known to cause such NDs as Huntington’s disease and spinocerebellar ataxias type 3 (SCA3). Here, we studied the clinical utility of a custom-made TGP that targets 199 NDs and 311 ND-associated genes on 118 undiagnosed patients. At least one known or likely pathogenic variation was found in 54 patients; 27 patients demonstrated clinical profiles that matched the variants; and 16 patients whose original diagnosis were refined. A high concordance of variant calling were observed when comparing the results from TGP and whole-exome sequencing of four patients. Our in-house STR detection algorithm has reached a specificity of 0.88 and a sensitivity of 0.82 in our SCA3 cohort. This study also uncovered a trove of novel and recurrent variants that may enrich the repertoire of ND-related genetic markers. We propose that a combined comprehensive TGPs-bioinformatics pipeline can improve the clinical diagnosis of NDs. |
| first_indexed | 2024-12-14T00:55:42Z |
| format | Article |
| id | doaj.art-f082d8da54b64c77956e54ed0d9bb7e0 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-14T00:55:42Z |
| publishDate | 2019-12-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Neuroscience |
| spelling | doaj.art-f082d8da54b64c77956e54ed0d9bb7e02022-12-21T23:23:35ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2019-12-011310.3389/fnins.2019.01324496081A Targeted Gene Panel That Covers Coding, Non-coding and Short Tandem Repeat Regions Improves the Diagnosis of Patients With Neurodegenerative DiseasesAllen Chi-Shing Yu0Allen Chi-Shing Yu1Aldrin Kay-Yuen Yim2Aldrin Kay-Yuen Yim3Anne Yin-Yan Chan4Liz Y. P. Yuen5Wing Chi Au6Wing Chi Au7Timothy H. T. Cheng8Xiao Lin9Jing-Woei Li10Larry W. L. Chan11Vincent C. T. Mok12Vincent C. T. Mok13Ting-Fung Chan14Ting-Fung Chan15Ting-Fung Chan16Ho Yin Edwin Chan17Ho Yin Edwin Chan18Ho Yin Edwin Chan19Codex Genetics Limited, Shatin, Hong KongSchool of Life Sciences, The Chinese University of Hong Kong, Shatin, ChinaCodex Genetics Limited, Shatin, Hong KongComputational and System Biology Program, Washington University School of Medicine, Saint Louis, MO, United StatesDivision of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, ChinaDepartment of Chemical Pathology, The Chinese University of Hong Kong, Shatin, ChinaDivision of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, ChinaGerald Choa Neuroscience Centre, The Chinese University of Hong Kong, Shatin, ChinaDepartment of Chemical Pathology, The Chinese University of Hong Kong, Shatin, ChinaSchool of Life Sciences, The Chinese University of Hong Kong, Shatin, ChinaCodex Genetics Limited, Shatin, Hong KongAlice Ho Miu Ling Nethersole Hospital, Tai Po, Hong KongDivision of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, ChinaGerald Choa Neuroscience Centre, The Chinese University of Hong Kong, Shatin, ChinaCodex Genetics Limited, Shatin, Hong KongSchool of Life Sciences, The Chinese University of Hong Kong, Shatin, ChinaGerald Choa Neuroscience Centre, The Chinese University of Hong Kong, Shatin, ChinaCodex Genetics Limited, Shatin, Hong KongSchool of Life Sciences, The Chinese University of Hong Kong, Shatin, ChinaGerald Choa Neuroscience Centre, The Chinese University of Hong Kong, Shatin, ChinaGenetic testing for neurodegenerative diseases (NDs) is highly challenging because of genetic heterogeneity and overlapping manifestations. Targeted-gene panels (TGPs), coupled with next-generation sequencing (NGS), can facilitate the profiling of a large repertoire of ND-related genes. Due to the technical limitations inherent in NGS and TGPs, short tandem repeat (STR) variations are often ignored. However, STR expansions are known to cause such NDs as Huntington’s disease and spinocerebellar ataxias type 3 (SCA3). Here, we studied the clinical utility of a custom-made TGP that targets 199 NDs and 311 ND-associated genes on 118 undiagnosed patients. At least one known or likely pathogenic variation was found in 54 patients; 27 patients demonstrated clinical profiles that matched the variants; and 16 patients whose original diagnosis were refined. A high concordance of variant calling were observed when comparing the results from TGP and whole-exome sequencing of four patients. Our in-house STR detection algorithm has reached a specificity of 0.88 and a sensitivity of 0.82 in our SCA3 cohort. This study also uncovered a trove of novel and recurrent variants that may enrich the repertoire of ND-related genetic markers. We propose that a combined comprehensive TGPs-bioinformatics pipeline can improve the clinical diagnosis of NDs.https://www.frontiersin.org/article/10.3389/fnins.2019.01324/fullneurodegenerative diseasesundiagnosed diseasesgene panelshort tandem repeatclinical decision supporthigh-throughput sequencing |
| spellingShingle | Allen Chi-Shing Yu Allen Chi-Shing Yu Aldrin Kay-Yuen Yim Aldrin Kay-Yuen Yim Anne Yin-Yan Chan Liz Y. P. Yuen Wing Chi Au Wing Chi Au Timothy H. T. Cheng Xiao Lin Jing-Woei Li Larry W. L. Chan Vincent C. T. Mok Vincent C. T. Mok Ting-Fung Chan Ting-Fung Chan Ting-Fung Chan Ho Yin Edwin Chan Ho Yin Edwin Chan Ho Yin Edwin Chan A Targeted Gene Panel That Covers Coding, Non-coding and Short Tandem Repeat Regions Improves the Diagnosis of Patients With Neurodegenerative Diseases Frontiers in Neuroscience neurodegenerative diseases undiagnosed diseases gene panel short tandem repeat clinical decision support high-throughput sequencing |
| title | A Targeted Gene Panel That Covers Coding, Non-coding and Short Tandem Repeat Regions Improves the Diagnosis of Patients With Neurodegenerative Diseases |
| title_full | A Targeted Gene Panel That Covers Coding, Non-coding and Short Tandem Repeat Regions Improves the Diagnosis of Patients With Neurodegenerative Diseases |
| title_fullStr | A Targeted Gene Panel That Covers Coding, Non-coding and Short Tandem Repeat Regions Improves the Diagnosis of Patients With Neurodegenerative Diseases |
| title_full_unstemmed | A Targeted Gene Panel That Covers Coding, Non-coding and Short Tandem Repeat Regions Improves the Diagnosis of Patients With Neurodegenerative Diseases |
| title_short | A Targeted Gene Panel That Covers Coding, Non-coding and Short Tandem Repeat Regions Improves the Diagnosis of Patients With Neurodegenerative Diseases |
| title_sort | targeted gene panel that covers coding non coding and short tandem repeat regions improves the diagnosis of patients with neurodegenerative diseases |
| topic | neurodegenerative diseases undiagnosed diseases gene panel short tandem repeat clinical decision support high-throughput sequencing |
| url | https://www.frontiersin.org/article/10.3389/fnins.2019.01324/full |
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