Background: The genetic cause of hypertrophic cardiomyopathy remains unexplained in a substantial proportion of cases. Formin homology 2 domain containing 3 (FHOD3) gene is implicated in sarcomere organization, myofibrillogenesis, and maintenance of the contractile apparatus in cardiomyocytes. FHOD3 may have a role in the pathogenesis of cardiac hypertrophy, but has not been implicated in hypertrophic cardiomyopathy.
Purpose: To determine the relation between FHOD3 mutations and the development of Hypertrophic Cardiomyopathy.
Methods: FHOD3 was sequenced by NGS in 3,189 HCM probands; 1,915 patients with other cardiomyopathies or sudden death, and 2,777 disease-controls. We evaluated altering protein candidate variants (minor allele frequency ≤0.005% in controls); carriers of other variants in sarcomeric genes were excluded. We evaluated cosegregation of FHOD3 variants with HCM in families that accepted to participate by calculating the LOD score. Clinical characteristics and outcomes were assessed in carriers of pathogenic or likely pathogenic variants in FHOD3 according to ACMG criteria.
Results: We identified 107 FHOD3 candidate variants in 139 probands. Frequency was significantly higher in HCM probands (76 of 3,189 [2.4%]) than in disease-controls (20 of 2,777 [0.7%]; p<0.001) or in gnomAD database (1,731 of 138,606 [1.2%]; p<0.001). FHOD3 mutations cosegregated with HCM in several families with a combined LOD score of 7.92 (very strong cosegregation). Half of the disease-causing variants were clustered in a narrow conserved coiled-coil domain (amino-acids 622–655); the odds ratio for HCM in this region was 21.8 versus disease-controls (95%IC: 1.3–36.9; p<0.001) and 10.9 against gnomAD (95%IC: 5.6–21.1; p<0.001). Of the rest of the disease-causing variants, the majority were located in the diaphanous auto-regulatory domain (DAD) and inhibitory domains (DID), or their surrounding residues (fig. 1A); these domains have been implicated in the pathogenesis of cardiac hypertrophy induced by angiotensin II (fig. 1B).
Most HCM patients with FHOD3 mutations were diagnosed after age 30 years and two thirds (66%) were males. 82% had asymmetric septal hypertrophy (mean 18.8±5 mm). Left-ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%. Annual cardiovascular death incidence between ages 20 to 70 was 0.6%.
Conclusions: FHOD3 is a novel disease causing gene in hypertrophic cardiomyopathy, accounting for at least 1–2% of cases. The phenotype and the rate of cardiovascular events are similar to that described for unselected cohorts. The FHOD3 gene should be routinely included in hypertrophic cardiomyopathy genetic testing panels.