Variant Spectrum of Formin Homology 2 Domain‐Containing 3 Gene in Chinese Patients With Hypertrophic Cardiomyopathy

BACKGROUND: The FHOD3 (formin homology 2 domain‐containing 3) gene has recently been identified as a causative gene of hypertrophic cardiomyopathy (HCM). However, the pathogenicity of FHOD3 variants remains to be evaluated. This study analyzed the spectrum of FHOD3 variants in a large HCM and control cohort, and explored its correlation with the disease. METHODS AND RESULTS: The genetic analysis of FHOD3 was performed using the whole exome sequencing data from 1000 patients with HCM and 761 controls without HCM. A total of 37 FHOD3 candidate variants were identified, including 25 missense variants and 2 truncating variants. In detail, there were 27 candidate variants detected in 33 (3.3%) patients with HCM, which was significantly higher than in the 12 controls (3.3% versus 1.6%; odds ratio, 2.13; P<0.05). On the basis of familial segregation, we identified one truncating variant (c.1286+2delT) as a causal variant in 4 patients. Furthermore, the FHOD3 candidate variant experienced significantly more risk of cardiovascular death and all‐cause death (adjusted hazard ratio [HR], 3.71; 95%, 1.32–8.59; P=0.016; and adjusted HR, 3.02; 95% CI, 1.09–6.85; P=0.035, respectively). CONCLUSIONS: Our study suggests that FHOD3 is a causal gene for HCM, and that the presence of FHOD3 candidate variants is an independent risk for cardiovascular death and all‐cause death in HCM.