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Clinical validity assessment of genes for inclusion in multi‐gene panel testing: A systematic approach
BACKGROUND: Advances in sequencing technology have led to expanded use of multi‐gene panel tests (MGPTs) for clinical diagnostics. Well‐designed MGPTs must balance increased detection of clinically significant findings while mitigating the increase in variants of uncertain significance (VUS). To max...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503028/ https://www.ncbi.nlm.nih.gov/pubmed/30900393 http://dx.doi.org/10.1002/mgg3.630 |
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author | Zion, Tricia N. Wayburn, Bess Darabi, Sourat Lamb Thrush, Devon Smith, Erica D. Johnston, Tami Martin, Brissa Hagman, Kelly D. F. Parra, Melissa Antolik, Christian |
author_facet | Zion, Tricia N. Wayburn, Bess Darabi, Sourat Lamb Thrush, Devon Smith, Erica D. Johnston, Tami Martin, Brissa Hagman, Kelly D. F. Parra, Melissa Antolik, Christian |
author_sort | Zion, Tricia N. |
collection | PubMed |
description | BACKGROUND: Advances in sequencing technology have led to expanded use of multi‐gene panel tests (MGPTs) for clinical diagnostics. Well‐designed MGPTs must balance increased detection of clinically significant findings while mitigating the increase in variants of uncertain significance (VUS). To maximize clinical utililty, design of such panels should include comprehensive gene vetting using a standardized clinical validity (CV) scoring system. METHODS: To assess the impact of CV‐based gene vetting on MGPT results, data from MGPTs for cardiovascular indications were retrospectively analyzed. Using our CV scoring system, genes were categorized as having definitive, strong, moderate, or limited evidence. The rates of reported pathogenic or likely pathogenic variants and VUS were then determined for each CV category. RESULTS: Of 106 total genes, 42% had definitive, 17% had strong, 29% had moderate, and 12% had limited CV. The detection rate of variants classified as pathogenic or likely pathogenic was higher for genes with greater CV, while the VUS rate showed an inverse relationship with CV score. No pathogenic or likely pathogenic findings were observed in genes with a limited CV. CONCLUSION: These results demonstrate the importance of a standardized, evidence‐based vetting process to establish CV for genes on MGPTs. Using our proposed system may help to increase the detection rate while mitigating higher VUS rates. |
format | Online Article Text |
id | pubmed-6503028 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-65030282019-05-10 Clinical validity assessment of genes for inclusion in multi‐gene panel testing: A systematic approach Zion, Tricia N. Wayburn, Bess Darabi, Sourat Lamb Thrush, Devon Smith, Erica D. Johnston, Tami Martin, Brissa Hagman, Kelly D. F. Parra, Melissa Antolik, Christian Mol Genet Genomic Med Original Articles BACKGROUND: Advances in sequencing technology have led to expanded use of multi‐gene panel tests (MGPTs) for clinical diagnostics. Well‐designed MGPTs must balance increased detection of clinically significant findings while mitigating the increase in variants of uncertain significance (VUS). To maximize clinical utililty, design of such panels should include comprehensive gene vetting using a standardized clinical validity (CV) scoring system. METHODS: To assess the impact of CV‐based gene vetting on MGPT results, data from MGPTs for cardiovascular indications were retrospectively analyzed. Using our CV scoring system, genes were categorized as having definitive, strong, moderate, or limited evidence. The rates of reported pathogenic or likely pathogenic variants and VUS were then determined for each CV category. RESULTS: Of 106 total genes, 42% had definitive, 17% had strong, 29% had moderate, and 12% had limited CV. The detection rate of variants classified as pathogenic or likely pathogenic was higher for genes with greater CV, while the VUS rate showed an inverse relationship with CV score. No pathogenic or likely pathogenic findings were observed in genes with a limited CV. CONCLUSION: These results demonstrate the importance of a standardized, evidence‐based vetting process to establish CV for genes on MGPTs. Using our proposed system may help to increase the detection rate while mitigating higher VUS rates. John Wiley and Sons Inc. 2019-03-21 /pmc/articles/PMC6503028/ /pubmed/30900393 http://dx.doi.org/10.1002/mgg3.630 Text en © 2019 Ambry Genetics. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Zion, Tricia N. Wayburn, Bess Darabi, Sourat Lamb Thrush, Devon Smith, Erica D. Johnston, Tami Martin, Brissa Hagman, Kelly D. F. Parra, Melissa Antolik, Christian Clinical validity assessment of genes for inclusion in multi‐gene panel testing: A systematic approach |
title | Clinical validity assessment of genes for inclusion in multi‐gene panel testing: A systematic approach |
title_full | Clinical validity assessment of genes for inclusion in multi‐gene panel testing: A systematic approach |
title_fullStr | Clinical validity assessment of genes for inclusion in multi‐gene panel testing: A systematic approach |
title_full_unstemmed | Clinical validity assessment of genes for inclusion in multi‐gene panel testing: A systematic approach |
title_short | Clinical validity assessment of genes for inclusion in multi‐gene panel testing: A systematic approach |
title_sort | clinical validity assessment of genes for inclusion in multi‐gene panel testing: a systematic approach |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503028/ https://www.ncbi.nlm.nih.gov/pubmed/30900393 http://dx.doi.org/10.1002/mgg3.630 |
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