Amit V Khera1, Heather Mason-Suares2, Deanna Brockman3, Minxian Wang4, Martin J VanDenburgh5, Ozlem Senol-Cosar6, Candace Patterson4, Christopher Newton-Cheh7, Seyedeh M Zekavat4, Julie Pester5, Daniel I Chasman5, Christopher Kabrhel8, Majken K Jensen9, JoAnn E Manson5, J Michael Gaziano10, Kent D Taylor11, Nona Sotoodehnia12, Wendy S Post13, Stephen S Rich14, Jerome I Rotter11, Eric S Lander15, Heidi L Rehm16, Kenney Ng17, Anthony Philippakis4, Matthew Lebo2, Christine M Albert18, Sekar Kathiresan19. 1. Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts; Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Electronic address: avkhera@mgh.harvard.edu. 2. Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, Massachusetts. 3. Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts. 4. Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts. 5. Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 6. Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, Massachusetts; Janssen Pharmaceuticals, Cambridge, Massachusetts. 7. Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts; Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts. 8. Department of Emergency Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 9. Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 10. Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Division of Aging, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 11. The Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California. 12. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington. 13. Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. 14. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia. 15. Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Biology, MIT, Cambridge, Massachusetts; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts. 16. Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts. 17. Center for Computational Health, IBM Research, Cambridge, Massachusetts. 18. Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address: Christine.Albert@cshs.org. 19. Verve Therapeutics, Cambridge, Massachusetts.
Abstract
BACKGROUND: Sudden cardiac death occurs in ∼220,000 U.S. adults annually, the majority of whom have no prior symptoms or cardiovascular diagnosis. Rare pathogenic DNA variants in any of 49 genes can pre-dispose to 4 important causes of sudden cardiac death: cardiomyopathy, coronary artery disease, inherited arrhythmia syndrome, and aortopathy or aortic dissection. OBJECTIVES: This study assessed the prevalence of rare pathogenic variants in sudden cardiac death cases versus controls, and the prevalence and clinical importance of such mutations in an asymptomatic adult population. METHODS: The authors performed whole-exome sequencing in a case-control cohort of 600 adult-onset sudden cardiac death cases and 600 matched controls from 106,098 participants of 6 prospective cohort studies. Observed DNA sequence variants in any of 49 genes with known association to cardiovascular disease were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status. In an independent population of 4,525 asymptomatic adult participants of a prospective cohort study, the authors performed whole-genome sequencing and determined the prevalence of pathogenic or likely pathogenic variants and prospective association with cardiovascular death. RESULTS: Among the 1,200 sudden cardiac death cases and controls, the authors identified 5,178 genetic variants and classified 14 as pathogenic or likely pathogenic. These 14 variants were present in 15 individuals, all of whom had experienced sudden cardiac death-corresponding to a pathogenic variant prevalence of 2.5% in cases and 0% in controls (p < 0.0001). Among the 4,525 participants of the prospective cohort study, 41 (0.9%) carried a pathogenic or likely pathogenic variant and these individuals had 3.24-fold higher risk of cardiovascular death over a median follow-up of 14.3 years (p = 0.02). CONCLUSIONS: Gene sequencing identifies a pathogenic or likely pathogenic variant in a small but potentially important subset of adults experiencing sudden cardiac death; these variants are present in ∼1% of asymptomatic adults.
BACKGROUND:Sudden cardiac death occurs in ∼220,000 U.S. adults annually, the majority of whom have no prior symptoms or cardiovascular diagnosis. Rare pathogenic DNA variants in any of 49 genes can pre-dispose to 4 important causes of sudden cardiac death: cardiomyopathy, coronary artery disease, inherited arrhythmia syndrome, and aortopathy or aortic dissection. OBJECTIVES: This study assessed the prevalence of rare pathogenic variants in sudden cardiac death cases versus controls, and the prevalence and clinical importance of such mutations in an asymptomatic adult population. METHODS: The authors performed whole-exome sequencing in a case-control cohort of 600 adult-onset sudden cardiac death cases and 600 matched controls from 106,098 participants of 6 prospective cohort studies. Observed DNA sequence variants in any of 49 genes with known association to cardiovascular disease were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status. In an independent population of 4,525 asymptomatic adult participants of a prospective cohort study, the authors performed whole-genome sequencing and determined the prevalence of pathogenic or likely pathogenic variants and prospective association with cardiovascular death. RESULTS: Among the 1,200 sudden cardiac death cases and controls, the authors identified 5,178 genetic variants and classified 14 as pathogenic or likely pathogenic. These 14 variants were present in 15 individuals, all of whom had experienced sudden cardiac death-corresponding to a pathogenic variant prevalence of 2.5% in cases and 0% in controls (p < 0.0001). Among the 4,525 participants of the prospective cohort study, 41 (0.9%) carried a pathogenic or likely pathogenic variant and these individuals had 3.24-fold higher risk of cardiovascular death over a median follow-up of 14.3 years (p = 0.02). CONCLUSIONS: Gene sequencing identifies a pathogenic or likely pathogenic variant in a small but potentially important subset of adults experiencing sudden cardiac death; these variants are present in ∼1% of asymptomatic adults.
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