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

BACKGROUND The presence of variants in OBSCN was identified to be linked to hypertrophic cardiomyopathy (HCM), but whether OBSCN 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 OBSCN truncating variants, and the result was tested in a replication cohort consisting of 529 patients with HCM and 307 controls. The association of the OBSCN truncating variants with baseline characteristics and prognosis of patients with HCM were ascertained. RESULTS There were 28 qualifying truncating variants in the OBSCN gene detected in 26 (2.6%) patients with HCM and 6 (0.8%) controls. The OBSCN 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 without OBSCN truncating variants shared similar demographic and echocardiographic variables at baseline. During 3.3±2.4 years (4795 patient-years) follow-up, the patients with OBSCN 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 that OBSCN truncating variants contributed to the disease-onset of HCM, and increased the risk of malignant events in patients with HCM.