Multiple rare variants in hypertrophic cardiomyopathy were associated with a family history of sudden cardiac death (OR 3.5; 95% CI 1.3-9.9; P=0.02) and worse event-free survival (P=0.008).
Observational (n=412)
Does the presence of multiple rare variants worsen disease onset and event-free survival in patients with hypertrophic cardiomyopathy?
Multiple rare variants in hypertrophic cardiomyopathy patients, seen in 4% on targeted panels, contribute to earlier disease onset and worse cardiac event-free survival, supporting a cumulative variant hypothesis.
Effect estimate: OR 3.5 (95% CI 1.3-9.9)
p-value: p=0.02
Background— Multiple likely pathogenic/pathogenic (LP/P; ≥2) variants in patients with hypertrophic cardiomyopathy were described 10 years ago with a prevalence of 5%. We sought to re-examine the significance of multiple rare variants in patients with hypertrophic cardiomyopathy in the setting of comprehensive and targeted panels. Methods and Results— Of 758 hypertrophic cardiomyopathy probands, we included 382 with ≥45 cardiomyopathy genes screened. There were 224 (59%) with ≥1 rare variant (allele frequency ≤0.02%). Variants were analyzed using varying sized gene panels to represent comprehensive or targeted testing. Based on a 45-gene panel, 127 (33%) had a LP/P variant, 139 (36%) had variants of uncertain significance, and 66 (17%) had multiple rare variants. A targeted 8-gene panel yielded 125 (32%) LP/P variants, 52 (14%) variants of uncertain significance, and 14 (4%) had multiple rare variants. No proband had 2 LP/P variants. Including affected family members (total n=412), cluster-adjusted analyses identified a phenotype effect, with younger age (odds ratio, 0.95; 95% confidence interval, 0.92–0.98; P =0.004) and family history of sudden cardiac death (odds ratio, 3.5; 95% confidence interval, 1.3–9.9; P =0.02) significantly more likely in multiple versus single variant patients when considering an 8-gene panel but not larger panels. Those with multiple variants had worse event-free survival from all-cause death, cardiac transplantation, and cardiac arrest (log-rank P =0.008). Conclusions— No proband had multiple LP/P variants in contrast to previous reports. However, multiple rare variants regardless of classification were seen in 4% and contributed to earlier disease onset and cardiac events. Our findings support a cumulative variant hypothesis in hypertrophic cardiomyopathy.
Burns et al. (Tue,) conducted a observational in Hypertrophic cardiomyopathy (n=412). Multiple rare variants vs. Single variant was evaluated on Family history of sudden cardiac death (OR 3.5, 95% CI 1.3-9.9, p=0.02). Multiple rare variants in hypertrophic cardiomyopathy were associated with a family history of sudden cardiac death (OR 3.5; 95% CI 1.3-9.9; P=0.02) and worse event-free survival (P=0.008).
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