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Determining the Likelihood of Disease Pathogenicity Among Incidentally Identified Genetic Variants in Rare Dilated Cardiomyopathy‐Associated Genes
BACKGROUND: As utilization of clinical exome sequencing (ES) has expanded, criteria for evaluating the diagnostic weight of incidentally identified variants are critical to guide clinicians and researchers. This is particularly important in genes associated with dilated cardiomyopathy (DCM), which c...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9673717/ https://www.ncbi.nlm.nih.gov/pubmed/36129056 http://dx.doi.org/10.1161/JAHA.122.025257 |
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author | Yang, Qixin Berkman, Amy M. Ezekian, Jordan E. Rosamilia, Michael Rosenfeld, Jill A. Liu, Pengfei Landstrom, Andrew P. |
author_facet | Yang, Qixin Berkman, Amy M. Ezekian, Jordan E. Rosamilia, Michael Rosenfeld, Jill A. Liu, Pengfei Landstrom, Andrew P. |
author_sort | Yang, Qixin |
collection | PubMed |
description | BACKGROUND: As utilization of clinical exome sequencing (ES) has expanded, criteria for evaluating the diagnostic weight of incidentally identified variants are critical to guide clinicians and researchers. This is particularly important in genes associated with dilated cardiomyopathy (DCM), which can cause heart failure and sudden death. We sought to compare the frequency and distribution of incidentally identified variants in DCM‐associated genes between a clinical referral cohort with those in control and known case cohorts to determine the likelihood of pathogenicity among those undergoing genetic testing for non‐DCM indications. METHODS AND RESULTS: A total of 39 rare, non‐TTN DCM‐associated genes were identified and evaluated from a clinical ES testing referral cohort (n=14 005, Baylor Genetic Laboratories) and compared with a DCM case cohort (n=9442) as well as a control cohort of population variants (n=141 456) derived from the gnomAD database. Variant frequencies in each cohort were compared. Signal‐to‐noise ratios were calculated comparing the DCM and ES cohort with the gnomAD cohort. The likely pathogenic/pathogenic variant yield in the DCM cohort (8.2%) was significantly higher than in the ES cohort (1.9%). Based on signal‐to‐noise and correlation analysis, incidental variants found in FLNC, RBM20, MYH6, DSP, ABCC9, JPH2, and NEXN had the greatest chance of being DCM‐associated. CONCLUSIONS: The distribution of pathogenic variants between the ES cohort and the DCM case cohort was gene specific, and variants found in the ES cohort were similar to variants found in the control cohort. Incidentally identified variants in specific genes are more associated with DCM than others. |
format | Online Article Text |
id | pubmed-9673717 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-96737172022-11-21 Determining the Likelihood of Disease Pathogenicity Among Incidentally Identified Genetic Variants in Rare Dilated Cardiomyopathy‐Associated Genes Yang, Qixin Berkman, Amy M. Ezekian, Jordan E. Rosamilia, Michael Rosenfeld, Jill A. Liu, Pengfei Landstrom, Andrew P. J Am Heart Assoc Original Research BACKGROUND: As utilization of clinical exome sequencing (ES) has expanded, criteria for evaluating the diagnostic weight of incidentally identified variants are critical to guide clinicians and researchers. This is particularly important in genes associated with dilated cardiomyopathy (DCM), which can cause heart failure and sudden death. We sought to compare the frequency and distribution of incidentally identified variants in DCM‐associated genes between a clinical referral cohort with those in control and known case cohorts to determine the likelihood of pathogenicity among those undergoing genetic testing for non‐DCM indications. METHODS AND RESULTS: A total of 39 rare, non‐TTN DCM‐associated genes were identified and evaluated from a clinical ES testing referral cohort (n=14 005, Baylor Genetic Laboratories) and compared with a DCM case cohort (n=9442) as well as a control cohort of population variants (n=141 456) derived from the gnomAD database. Variant frequencies in each cohort were compared. Signal‐to‐noise ratios were calculated comparing the DCM and ES cohort with the gnomAD cohort. The likely pathogenic/pathogenic variant yield in the DCM cohort (8.2%) was significantly higher than in the ES cohort (1.9%). Based on signal‐to‐noise and correlation analysis, incidental variants found in FLNC, RBM20, MYH6, DSP, ABCC9, JPH2, and NEXN had the greatest chance of being DCM‐associated. CONCLUSIONS: The distribution of pathogenic variants between the ES cohort and the DCM case cohort was gene specific, and variants found in the ES cohort were similar to variants found in the control cohort. Incidentally identified variants in specific genes are more associated with DCM than others. John Wiley and Sons Inc. 2022-09-21 /pmc/articles/PMC9673717/ /pubmed/36129056 http://dx.doi.org/10.1161/JAHA.122.025257 Text en © 2022 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Research Yang, Qixin Berkman, Amy M. Ezekian, Jordan E. Rosamilia, Michael Rosenfeld, Jill A. Liu, Pengfei Landstrom, Andrew P. Determining the Likelihood of Disease Pathogenicity Among Incidentally Identified Genetic Variants in Rare Dilated Cardiomyopathy‐Associated Genes |
title | Determining the Likelihood of Disease Pathogenicity Among Incidentally Identified Genetic Variants in Rare Dilated Cardiomyopathy‐Associated Genes |
title_full | Determining the Likelihood of Disease Pathogenicity Among Incidentally Identified Genetic Variants in Rare Dilated Cardiomyopathy‐Associated Genes |
title_fullStr | Determining the Likelihood of Disease Pathogenicity Among Incidentally Identified Genetic Variants in Rare Dilated Cardiomyopathy‐Associated Genes |
title_full_unstemmed | Determining the Likelihood of Disease Pathogenicity Among Incidentally Identified Genetic Variants in Rare Dilated Cardiomyopathy‐Associated Genes |
title_short | Determining the Likelihood of Disease Pathogenicity Among Incidentally Identified Genetic Variants in Rare Dilated Cardiomyopathy‐Associated Genes |
title_sort | determining the likelihood of disease pathogenicity among incidentally identified genetic variants in rare dilated cardiomyopathy‐associated genes |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9673717/ https://www.ncbi.nlm.nih.gov/pubmed/36129056 http://dx.doi.org/10.1161/JAHA.122.025257 |
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