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

Background: The presence of variants inOBSCN was identified to be linked to hypertrophic cardiomyopathy (HCM), but whetherOBSCN 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 forOBSCN truncating variants, and the result was tested in a replication cohort consisting of 529 patients with HCM and 307 controls. The association of theOBSCN truncating variants with baseline characteristics and prognosis of patients with HCM were ascertained.Results: There were 28 qualifying truncating variants in theOBSCN gene detected in 26 (2.6%) patients with HCM and 6 (0.8%) controls. TheOBSCN truncating variants were more prevalent in patients with HCM than controls (odds ratio, 3.4,P =0.004). This association was confirmed in the replication cohort (odds ratio, 3.8,P =0.024). The combined effects of the two cohorts estimated the odds ratio to be 3.58 (P <0.001). Patients with or withoutOBSCN truncating variants shared similar demographic and echocardiographic variables at baseline. During 3.3±2.4 years (4795 patient-years) follow-up, the patients withOBSCN truncating variants were more likely to experience cardiovascular death (adjusted hazard ratio, 3.1 [95% CI, 1.40–6.70],P =0.005) and all-cause death (adjusted hazard ratio, 2.63 [95% CI, 1.21–5.71],P =0.015).Conclusions: Our data indicated thatOBSCN truncating variants contributed to the disease-onset of HCM, and increased the risk of malignant events in patients with HCM.