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 analyzed...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-02-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.119.013808 |
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| author | Tess D. Pottinger Megan J. Puckelwartz Lorenzo L. Pesce Avery Robinson Samuel Kearns Jennifer A. Pacheco Laura J. Rasmussen‐Torvik Maureen E. Smith Rex Chisholm Elizabeth M. McNally |
| author_facet | Tess D. Pottinger Megan J. Puckelwartz Lorenzo L. Pesce Avery Robinson Samuel Kearns Jennifer A. Pacheco Laura J. Rasmussen‐Torvik Maureen E. Smith Rex Chisholm Elizabeth M. McNally |
| author_sort | Tess D. Pottinger |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-18T10:50:46Z |
| format | Article |
| id | doaj.art-4c41541b75f44159a997a45e78137fd0 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-18T10:50:46Z |
| publishDate | 2020-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-4c41541b75f44159a997a45e78137fd02022-12-21T21:10:27ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802020-02-019310.1161/JAHA.119.013808Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank ParticipantsTess D. Pottinger0Megan J. Puckelwartz1Lorenzo L. Pesce2Avery Robinson3Samuel Kearns4Jennifer A. Pacheco5Laura J. Rasmussen‐Torvik6Maureen E. Smith7Rex Chisholm8Elizabeth M. McNally9Center for Genetic Medicine Northwestern University Feinberg School of Medicine Chicago ILCenter for Genetic Medicine Northwestern University Feinberg School of Medicine Chicago ILComputation Institute University of Chicago Chicago ILCenter for Genetic Medicine Northwestern University Feinberg School of Medicine Chicago ILCenter for Genetic Medicine Northwestern University Feinberg School of Medicine Chicago ILCenter for Genetic Medicine Northwestern University Feinberg School of Medicine Chicago ILDepartment of Preventive Medicine Northwestern University Feinberg School of Medicine Chicago ILCenter for Genetic Medicine Northwestern University Feinberg School of Medicine Chicago ILCenter for Genetic Medicine Northwestern University Feinberg School of Medicine Chicago ILCenter for Genetic Medicine Northwestern University Feinberg School of Medicine Chicago ILBackground 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.https://www.ahajournals.org/doi/10.1161/JAHA.119.013808biobankcardiomyopathyleft ventriclemedically actionable genesvariants of uncertain significance |
| spellingShingle | Tess D. Pottinger Megan J. Puckelwartz Lorenzo L. Pesce Avery Robinson Samuel Kearns Jennifer A. Pacheco Laura J. Rasmussen‐Torvik Maureen E. Smith Rex Chisholm Elizabeth M. McNally Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease biobank cardiomyopathy left ventricle medically actionable genes variants of uncertain significance |
| 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 | biobank cardiomyopathy left ventricle medically actionable genes variants of uncertain significance |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.119.013808 |
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