Key result
The p.Arg637Gln variant in FHOD3 was significantly enriched in patients with hypertrophic cardiomyopathy compared to internal controls (2.94% vs 0.59%; OR 5.40, 95% CI 4.11-7.09).
Why the study?
FHOD3 is a major non-sarcomeric gene linked to HCM, but biallelic variants associated with disease had not been described.
Does the p.Arg637Gln variant in the FHOD3 gene increase the risk and severity of hypertrophic cardiomyopathy?
Case-Control (n=22,806)
No
Does the p.Arg637Gln variant in the FHOD3 gene increase the risk and severity of hypertrophic cardiomyopathy?
Odds Ratio: 5.4 (95% CI 4.11–7.09)
Absolute Event Rate: 2.94% vs 0.59%
The p.Arg637Gln variant in FHOD3 acts as an intermediate-effect predisposing factor for HCM in heterozygotes and is associated with a severe, early-onset phenotype in homozygotes.
Homozygous carriers may warrant closer monitoring; leaves open validation before changing screening guidelines.
Formin homology 2 domain-containing 3 ( FHOD3 ) gene has emerged as one of the main non-sarcomeric genes associated with hypertrophic cardiomyopathy (HCM), but no cases of biallelic variants associated with disease have been described to date. From 2014 until 2021, FHOD3 was evaluated in our center by next-generation sequencing in 22 806 consecutive unrelated probands. The p.Arg637Gln variant in FHOD3 was enriched in our HCM cohort (284 of 9668 probands; 2.94%) compared with internal controls (64 of 11 480; 0.59%) and gnomAD controls (373 of 64 409; 0.58%), with ORs of 5.40 (95% CI: 4.11 to 7.09) and 5.19 (95% CI: 4.44 to 6.07). The variant affects a highly conserved residue localised in a supercoiled alpha helix considered a clustering site for HCM variants, and in heterozygosis can act as a predisposing factor (intermediate-effect variant) for HCM, with an estimated penetrance of around 1%. Additionally, seven homozygous carriers of p.Arg637Gln in FHOD3 were identified. All but one (unaffected) showed an early presentation and a severe HCM phenotype. All this information suggest that p.Arg637Gln variant in FHOD3 is a low-penetrant variant, with an intermediate effect, that contributes to the development of HCM in simple heterozygosis, being associated with a more severe phenotype in homozygous carriers.
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Piqueras‐Flores et al. (2023) conducted a case-control in Hypertrophic cardiomyopathy (HCM) (n=22,806). p.Arg637Gln variant in FHOD3 vs. Internal controls and gnomAD controls was evaluated on Hypertrophic cardiomyopathy (OR 5.40, 95% CI 4.11-7.09). The p.Arg637Gln variant in FHOD3 was significantly enriched in patients with hypertrophic cardiomyopathy compared to internal controls (2.94% vs 0.59%; OR 5.40, 95% CI 4.11-7.09).
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