Misannotation of multiple-nucleotide variants risks misdiagnosis [version 2; peer review: 2 approved]
Multiple Nucleotide Variants (MNVs) are miscalled by the most widely utilised next generation sequencing analysis (NGS) pipelines, presenting the potential for missing diagnoses. These variants, which should be treated as a single insertion-deletion mutation event, are commonly called as separate si...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wellcome
2020-01-01
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| Series: | Wellcome Open Research |
| Online Access: | https://wellcomeopenresearch.org/articles/4-145/v2 |
| _version_ | 1818291362578038784 |
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| author | Matthew N. Wakeling Thomas W. Laver Kevin Colclough Andrew Parish Sian Ellard Emma L. Baple |
| author_facet | Matthew N. Wakeling Thomas W. Laver Kevin Colclough Andrew Parish Sian Ellard Emma L. Baple |
| author_sort | Matthew N. Wakeling |
| collection | DOAJ |
| description | Multiple Nucleotide Variants (MNVs) are miscalled by the most widely utilised next generation sequencing analysis (NGS) pipelines, presenting the potential for missing diagnoses. These variants, which should be treated as a single insertion-deletion mutation event, are commonly called as separate single nucleotide variants. This can result in misannotation, incorrect amino acid predictions and potentially false positive and false negative diagnostic results. Using simulated data and re-analysis of sequencing data from a diagnostic targeted gene panel, we demonstrate that the widely adopted pipeline, GATK best practices, results in miscalling of MNVs and that alternative tools can call these variants correctly. The adoption of calling methods that annotate MNVs correctly would present a solution for individual laboratories, however GATK best practices are the basis for important public resources such as the gnomAD database. We suggest integrating a solution into these guidelines would be the optimal approach. |
| first_indexed | 2024-12-13T02:42:52Z |
| format | Article |
| id | doaj.art-53f8647455ca4391b4205e24e2065cb6 |
| institution | Directory Open Access Journal |
| issn | 2398-502X |
| language | English |
| last_indexed | 2024-12-13T02:42:52Z |
| publishDate | 2020-01-01 |
| publisher | Wellcome |
| record_format | Article |
| series | Wellcome Open Research |
| spelling | doaj.art-53f8647455ca4391b4205e24e2065cb62022-12-22T00:02:15ZengWellcomeWellcome Open Research2398-502X2020-01-01410.12688/wellcomeopenres.15420.217176Misannotation of multiple-nucleotide variants risks misdiagnosis [version 2; peer review: 2 approved]Matthew N. Wakeling0Thomas W. Laver1Kevin Colclough2Andrew Parish3Sian Ellard4Emma L. Baple5Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, Devon, EX2 5DW, UKInstitute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, Devon, EX2 5DW, UKMolecular Genetics Department, Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon, EX2 5DW, UKMolecular Genetics Department, Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon, EX2 5DW, UKInstitute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, Devon, EX2 5DW, UKInstitute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, Devon, EX2 5DW, UKMultiple Nucleotide Variants (MNVs) are miscalled by the most widely utilised next generation sequencing analysis (NGS) pipelines, presenting the potential for missing diagnoses. These variants, which should be treated as a single insertion-deletion mutation event, are commonly called as separate single nucleotide variants. This can result in misannotation, incorrect amino acid predictions and potentially false positive and false negative diagnostic results. Using simulated data and re-analysis of sequencing data from a diagnostic targeted gene panel, we demonstrate that the widely adopted pipeline, GATK best practices, results in miscalling of MNVs and that alternative tools can call these variants correctly. The adoption of calling methods that annotate MNVs correctly would present a solution for individual laboratories, however GATK best practices are the basis for important public resources such as the gnomAD database. We suggest integrating a solution into these guidelines would be the optimal approach.https://wellcomeopenresearch.org/articles/4-145/v2 |
| spellingShingle | Matthew N. Wakeling Thomas W. Laver Kevin Colclough Andrew Parish Sian Ellard Emma L. Baple Misannotation of multiple-nucleotide variants risks misdiagnosis [version 2; peer review: 2 approved] Wellcome Open Research |
| title | Misannotation of multiple-nucleotide variants risks misdiagnosis [version 2; peer review: 2 approved] |
| title_full | Misannotation of multiple-nucleotide variants risks misdiagnosis [version 2; peer review: 2 approved] |
| title_fullStr | Misannotation of multiple-nucleotide variants risks misdiagnosis [version 2; peer review: 2 approved] |
| title_full_unstemmed | Misannotation of multiple-nucleotide variants risks misdiagnosis [version 2; peer review: 2 approved] |
| title_short | Misannotation of multiple-nucleotide variants risks misdiagnosis [version 2; peer review: 2 approved] |
| title_sort | misannotation of multiple nucleotide variants risks misdiagnosis version 2 peer review 2 approved |
| url | https://wellcomeopenresearch.org/articles/4-145/v2 |
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