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Rare Genetic Variants Associated With Sudden Cardiac Death
Study Questions:
What is the prevalence of rare pathogenic variants in sudden cardiac death (SCD) cases versus controls, and the prevalence and clinical importance of such mutations in an asymptomatic adult population?
Methods:
The investigators performed whole-exome sequencing in a case-control cohort of 600 adult-onset SCD cases and 600 matched controls from 106,098 participants of six 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. The relationship of pathogenic variant status to incident cardiovascular death was determined using a Cox proportional hazards model adjusted for age, sex, and race.
Results:
Among the 1,200 SCD 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 SCD—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:
The authors concluded that gene sequencing identifies a pathogenic or likely pathogenic variant in a small but potentially important subset of adults experiencing SCD.
Perspective:
This study reports that pathogenic or likely pathogenic variants in any of 49 cardiovascular disease genes are present in a small but potentially important subset of adults experiencing SCD. Furthermore, such variants are present in approximately 1% of an adult population free of known cardiovascular disease and conferred a more than threefold increased risk of cardiovascular death in prospective follow-up. Additional studies are indicated to assess the utility and cost-effectiveness of integrating genetic testing into risk assessment algorithms for prevention of SCD in adults.
Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, Prevention, Implantable Devices, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias
Keywords: AHA Annual Scientific Sessions, Arrhythmias, Cardiac, AHA 19 Slides, Death, Sudden, Cardiac, Genetic Testing, Genomics, Mutation, Risk Assessment, Secondary Prevention
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