TY - JOUR
T1 - Rare Genetic Variants Associated With Sudden Cardiac Death in Adults
AU - Khera, Amit V.
AU - Mason-Suares, Heather
AU - Brockman, Deanna
AU - Wang, Minxian
AU - VanDenburgh, Martin J.
AU - Senol-Cosar, Ozlem
AU - Patterson, Candace
AU - Newton-Cheh, Christopher
AU - Zekavat, Seyedeh M.
AU - Pester, Julie
AU - Chasman, Daniel I.
AU - Kabrhel, Christopher
AU - Jensen, Majken K.
AU - Manson, Jo Ann E.
AU - Gaziano, J. Michael
AU - Taylor, Kent D.
AU - Sotoodehnia, Nona
AU - Post, Wendy S.
AU - Rich, Stephen S.
AU - Rotter, Jerome I.
AU - Lander, Eric S.
AU - Rehm, Heidi L.
AU - Ng, Kenney
AU - Philippakis, Anthony
AU - Lebo, Matthew
AU - Albert, Christine M.
AU - Kathiresan, Sekar
N1 - Publisher Copyright:
© 2019 American College of Cardiology Foundation
PY - 2019/11/26
Y1 - 2019/11/26
N2 - 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.
AB - 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.
KW - gene sequencing
KW - genomic medicine
KW - sudden cardiac death
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U2 - 10.1016/j.jacc.2019.08.1060
DO - 10.1016/j.jacc.2019.08.1060
M3 - Article
C2 - 31727422
AN - SCOPUS:85075426294
SN - 0735-1097
VL - 74
SP - 2623
EP - 2634
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 21
ER -