Cascade genetically tested relatives with pathogenic sarcomere variants had fewer repeat major adverse cardiac events than genotype positive probands (HR 4.0), but more than genotype negative relatives, during a mean 8.9 year follow up.
Cohort (n=276)
Yes
Do genotype-positive cascade-tested relatives of hypertrophic cardiomyopathy probands have a different risk of major adverse cardiac events compared to probands and genotype-negative relatives?
Genotype-positive cascade-tested relatives of hypertrophic cardiomyopathy probands have a milder phenotype and lower event rate than probands, but retain a significantly higher risk of adverse cardiac events than genotype-negative relatives, justifying their ongoing clinical follow-up.
Effect estimate: HR 4.0 with 95% CI 1.9 to 8.5 for probands vs cascade tested; HR 4.9 with 95% CI 1.9 to 8.5 for cascade/G+ vs cascade/G-; OR 11.9 (4.9 to 29.3) for lifetime incidence of MACE proband/G+ vs cascade/G+ (95% CI HR 4.0 (1.9 to 8.5), HR 4.9 (1.9 to 8.5), OR 11.9 (4.9 to 29.3))
p-value: p=<0.001
Objectives Cascade-tested relatives of individuals with pathogenic genetic variants in sarcomere genes causing hypertrophic cardiomyopathy are recommended. Little is known about the outcomes in cascade-identified relatives. We aimed to characterise the endpoints for these individuals. Methods A retrospective cohort case note evaluation of 64 families reviewed by NHS Tayside Clinical Genetics between January 2010 and December 2018 was conducted, identifying 280 patients. The primary endpoint of the study was the composite endpoint of the onset of a repeat major adverse cardiac event (MACE). Analysis of covariance was used to model marginal mean estimates for baseline interventricular size. Cox proportional hazards model was used to depict time to MACEs. Results Asymmetrical septal hypertrophy fulfilling diagnostic criteria on echocardiography was noted in 35.4% of cascade-tested individuals. Adjusted interventricular septal size for cascade-tested individuals with a positive genotype (13.9 mm; 95% CI (12.1 to 15.8)) was lower than that of probands with a pathogenic variant (22.1 mm; 95% CI (19.7 to 24.4); p<0.001) but higher than that of cascade-tested individuals with no genotype (12.3 mm; 95% CI (10.2 to 14.4); p<0.001). Adjusted multivariate event analysis demonstrated decreased risk of adverse cardiac events in cascade-identified individuals compared with probands with a genotype (HR 4.0; 95% CI (1.9 to 8.5); p<0.001) and increased risk compared with cascade-identified relatives without a genotype (HR 3.3 (1.2 to 9.1); p<0.001). Conclusion Our results demonstrate that cascade-tested individuals carrying a pathogenic sarcomere variant retain a degree of complication justifying their identification and follow-up.
Chaudhry et al. (2026) conducted a cohort in Adults over 18 years with hypertrophic cardiomyopathy or cascade-tested relatives carrying a pathogenic or likely pathogenic sarcomere variant (n=276). Cascade genetic testing and clinical follow-up for relatives of probands with pathogenic sarcomere gene variants causing hypertrophic cardiomyopathy vs. Probands with genotype positive hypertrophic cardiomyopathy was evaluated on Composite major adverse cardiac events (MACEs) including ICD insertion, heart failure, angina, atrial fibrillation/flutter, ventricular fibrillation, non-sustained ventricular tachycardia, aborted sudden cardiac death, and all-cause mortality (HR 4.0 with 95% CI 1.9 to 8.5 for probands vs cascade tested; HR 4.9 with 95% CI 1.9 to 8.5 for cascade/G+ vs cascade/G-; OR 11.9 (4.9 to 29.3) for lifetime incidence of MACE proband/G+ vs cascade/G+, 95% CI HR 4.0 (1.9 to 8.5), HR 4.9 (1.9 to 8.5), OR 11.9 (4.9 to 29.3), p=<0.001). Cascade genetically tested relatives with pathogenic sarcomere variants had fewer repeat major adverse cardiac events than genotype positive probands (HR 4.0), but more than genotype negative relatives, during a mean 8.9 year follow up.