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

Abstract

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.

Keywords: cardiovascular events; formin homology 2 domain‐containing 3; genetic testing; hypertrophic cardiomyopathy.

Figure 1. Cosegregation of FHOD3 (formin homology 2 domain‐containing 3) candidate variants with hypertrophic cardiomyopathy.

Individuals affected by left ventricular hypertrophy are indicated by black symbols. Unfilled symbols represent individuals without ventricular hypertrophy. Arrows indicate the probands. Circles represent women; squares represent men. Symbols with a slash through them indicate deceased subjects. The current age or the age at death is indicated to the upper right of each symbol. Numbers in parentheses indicate individuals without DNA available.

Figure 2. Cumulative Kaplan‐Meier analysis showing that FHOD3 (formin homology 2 domain‐containing 3) candidate variants were associated with a higher risk of cardiovascular death (A), sudden cardiac death (B), and all‐cause death (C).

P values were calculated using the log‐rank test.