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Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants
BACKGROUND: Genome sequencing coupled with electronic heath record data can uncover medically important genetic variation. Interpretation of rare genetic variation and its role in mediating cardiovascular phenotypes is confounded by variants of uncertain significance. METHODS AND RESULTS: We analyze...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033893/ https://www.ncbi.nlm.nih.gov/pubmed/32009526 http://dx.doi.org/10.1161/JAHA.119.013808 |
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author | Pottinger, Tess D. Puckelwartz, Megan J. Pesce, Lorenzo L. Robinson, Avery Kearns, Samuel Pacheco, Jennifer A. Rasmussen‐Torvik, Laura J. Smith, Maureen E. Chisholm, Rex McNally, Elizabeth M. |
author_facet | Pottinger, Tess D. Puckelwartz, Megan J. Pesce, Lorenzo L. Robinson, Avery Kearns, Samuel Pacheco, Jennifer A. Rasmussen‐Torvik, Laura J. Smith, Maureen E. Chisholm, Rex McNally, Elizabeth M. |
author_sort | Pottinger, Tess D. |
collection | PubMed |
description | BACKGROUND: Genome sequencing coupled with electronic heath record data can uncover medically important genetic variation. Interpretation of rare genetic variation and its role in mediating cardiovascular phenotypes is confounded by variants of uncertain significance. METHODS AND RESULTS: We analyzed the whole genome sequence of 900 racially and ethnically diverse biobank participants selected from a single US center. Participants were equally divided among European, African, Hispanic, and mixed races/ethnicities. We evaluated the American College of Medical Genetics and Genomics medically actionable list of 59 genes, focusing on the cardiac genes. Variation was interpreted using the most recent reports in ClinVar, a database of medically relevant human variation. We identified 19 individuals with pathogenic or likely pathogenic variants in cardiac actionable genes (2%) and found evidence of related clinical correlates in the electronic health record. Participants of African ancestry, compared with those of European ancestry, had more variants of uncertain significance in the medically actionable genes including the 30 cardiac actionable genes, even when normalized to total variant count per person. Longitudinal measures of left ventricle size from ≈400 biobank participants (1723 patient‐years) were correlated with genetic findings. The presence of ≥1 uncertain variant in the actionable cardiac genes and a cardiomyopathy diagnosis correlated with increased left ventricular internal diameter in diastole and in systole. In particular, MYBPC3 was identified as a gene with excess variants of uncertain significance. CONCLUSIONS: These data indicate that a subset of uncertain genetic variants may confer risk and should not be considered benign. |
format | Online Article Text |
id | pubmed-7033893 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-70338932020-02-27 Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants Pottinger, Tess D. Puckelwartz, Megan J. Pesce, Lorenzo L. Robinson, Avery Kearns, Samuel Pacheco, Jennifer A. Rasmussen‐Torvik, Laura J. Smith, Maureen E. Chisholm, Rex McNally, Elizabeth M. J Am Heart Assoc Original Research BACKGROUND: Genome sequencing coupled with electronic heath record data can uncover medically important genetic variation. Interpretation of rare genetic variation and its role in mediating cardiovascular phenotypes is confounded by variants of uncertain significance. METHODS AND RESULTS: We analyzed the whole genome sequence of 900 racially and ethnically diverse biobank participants selected from a single US center. Participants were equally divided among European, African, Hispanic, and mixed races/ethnicities. We evaluated the American College of Medical Genetics and Genomics medically actionable list of 59 genes, focusing on the cardiac genes. Variation was interpreted using the most recent reports in ClinVar, a database of medically relevant human variation. We identified 19 individuals with pathogenic or likely pathogenic variants in cardiac actionable genes (2%) and found evidence of related clinical correlates in the electronic health record. Participants of African ancestry, compared with those of European ancestry, had more variants of uncertain significance in the medically actionable genes including the 30 cardiac actionable genes, even when normalized to total variant count per person. Longitudinal measures of left ventricle size from ≈400 biobank participants (1723 patient‐years) were correlated with genetic findings. The presence of ≥1 uncertain variant in the actionable cardiac genes and a cardiomyopathy diagnosis correlated with increased left ventricular internal diameter in diastole and in systole. In particular, MYBPC3 was identified as a gene with excess variants of uncertain significance. CONCLUSIONS: These data indicate that a subset of uncertain genetic variants may confer risk and should not be considered benign. John Wiley and Sons Inc. 2020-02-03 /pmc/articles/PMC7033893/ /pubmed/32009526 http://dx.doi.org/10.1161/JAHA.119.013808 Text en © 2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Research Pottinger, Tess D. Puckelwartz, Megan J. Pesce, Lorenzo L. Robinson, Avery Kearns, Samuel Pacheco, Jennifer A. Rasmussen‐Torvik, Laura J. Smith, Maureen E. Chisholm, Rex McNally, Elizabeth M. Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants |
title | Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants |
title_full | Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants |
title_fullStr | Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants |
title_full_unstemmed | Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants |
title_short | Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants |
title_sort | pathogenic and uncertain genetic variants have clinical cardiac correlates in diverse biobank participants |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033893/ https://www.ncbi.nlm.nih.gov/pubmed/32009526 http://dx.doi.org/10.1161/JAHA.119.013808 |
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