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

Abstract

Background The <i>FHOD3</i> (formin homology 2 domain-containing 3) gene has recently been identified as a causative gene of hypertrophic cardiomyopathy (HCM). However, the pathogenicity of <i>FHOD3</i> variants remains to be evaluated. This study analyzed the spectrum of <i>FHOD3</i> variants in a large HCM and control cohort, and explored its correlation with the disease. Methods and Results The genetic analysis of <i>FHOD3</i> was performed using the whole exome sequencing data from 1000 patients with HCM and 761 controls without HCM. A total of 37 <i>FHOD3</i> 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; <i>P</i><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 <i>FHOD3</i> candidate variant experienced significantly more risk of cardiovascular death and all-cause death (adjusted hazard ratio [HR], 3.71; 95%, 1.32-8.59; <i>P</i>=0.016; and adjusted HR, 3.02; 95% CI, 1.09-6.85; <i>P=</i>0.035, respectively). Conclusions Our study suggests that <i>FHOD3</i> is a causal gene for HCM, and that the presence of <i>FHOD3</i> candidate variants is an independent risk for cardiovascular death and all-cause death in HCM.