Key result
Pathogenic cardiovascular gene variants linked to ~3-fold higher risk of CV death in asymptomatic adults.
Why the study?
Most sudden cardiac deaths occur without prior symptoms or cardiovascular diagnosis, prompting evaluation of the prevalence and clinical significance of rare pathogenic variants in 49 cardiovascular genes among cases versus controls and in asymptomatic adults.
Does the presence of rare pathogenic genetic variants in 49 cardiovascular genes increase the risk of sudden cardiac death and incident cardiovascular death in adults?
Observational (n=5,725)
Blinded variant classification
Yes
Does the presence of rare pathogenic genetic variants in 49 cardiovascular genes increase the risk of sudden cardiac death and incident cardiovascular death in adults?
Hazard Ratio: 3.24 (95% CI 1.2–8.79)
Absolute Event Rate: 9.8% vs 3.6%
p-value: p=0.02
Rare pathogenic genetic variants in cardiovascular disease genes are found in approximately 1% of asymptomatic adults and are associated with a significantly increased risk of sudden cardiac death and incident cardiovascular death.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Strikingly, all 15 of these pathogenic variants were in sudden cardiac death cases, with none in controls.”
Pathogenic variants were associated with sudden cardiac death; leaves open whether population screening improves outcomes.
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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Khera et al. (2019) conducted an observational in Sudden cardiac death (n=5,725). Rare pathogenic or likely pathogenic variants in 49 cardiovascular disease genes vs. Noncarriers (absence of pathogenic variants) was evaluated on Incident cardiovascular death (HR 3.24, 95% CI 1.20-8.79, p=0.02). Rare pathogenic genetic variants in cardiovascular disease genes were present in 2.5% of sudden cardiac death cases versus 0% of controls, and asymptomatic carriers had a significantly increased risk of cardiovascular death (HR 3.24).
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