Truncating Variants in Gene Associated With Disease-Onset and Outcomes of Hypertrophic Cardiomyopathy.

BACKGROUND

The presence of variants in was identified to be linked to hypertrophic cardiomyopathy (HCM), but whether truncating variants were associated with HCM remained unknown.

METHODS

Whole-exome sequencing was performed in 986 patients with HCM and 761 non-HCM controls to search for truncating variants, and the result was tested in a replication cohort consisting of 529 patients with HCM and 307 controls. The association of the truncating variants with baseline characteristics and prognosis of patients with HCM were ascertained.

RESULTS

There were 28 qualifying truncating variants in the gene detected in 26 (2.6%) patients with HCM and 6 (0.8%) controls. The truncating variants were more prevalent in patients with HCM than controls (odds ratio, 3.4, =0.004). This association was confirmed in the replication cohort (odds ratio, 3.8, =0.024). The combined effects of the two cohorts estimated the odds ratio to be 3.58 (<0.001). Patients with or without truncating variants shared similar demographic and echocardiographic variables at baseline. During 3.3±2.4 years (4795 patient-years) follow-up, the patients with truncating variants were more likely to experience cardiovascular death (adjusted hazard ratio, 3.1 [95% CI, 1.40-6.70], =0.005) and all-cause death (adjusted hazard ratio, 2.63 [95% CI, 1.21-5.71], =0.015).

CONCLUSIONS

Our data indicated that truncating variants contributed to the disease-onset of HCM, and increased the risk of malignant events in patients with HCM.