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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
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.
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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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