Formin homology domain containing 3 (fhod3) como nuevo gen causal de miocardiopatía hipertrófica

Abstract

Background: The genetic cause of hypertrophic cardiomyopathy (HCM) remains unexplained in a substantial proportion of cases. FHOD3 might have a role in the pathogenesis of cardiac hypertrophy. Objectives: To investigate the relation between FHOD3 mutations and the development of hypertrophic cardiomyopathy. Methods: FHOD3 was sequenced by NGS in HCM unrelated probands and patients with no evidence of cardiomyopathy (controls). We evaluated protein-altering candidate variants in FHOD3 for cosegregation in families, clinical characteristics, and outcomes. Results: The frequencies of rare candidate variants were significantly higher in patients with HCM than in controls. FHOD3 mutations cosegregated with HCM in several families. Disease-causing variants were clustered in two relevant regions: the exon 12, and the conserved coiled-coil domain (amino-acids 622-655) in exon 15. Patients were diagnosed after age 30 years and two-thirds were males; 82% had asymmetric septal hypertrophy. Events were rare before age 30, with an annual cardiovascular death incidence of 1% during follow-up. Conclusions: FHOD3 is a novel disease gene in HCM, accounting for approximately 1-2% of cases. The phenotype and the rate of cardiovascular events are similar to those reported in unselected cohorts. The FHOD3 gene should be routinely included in hypertrophic cardiomyopathy genetic testing panels.