FHOD3 – Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant cardiac disease characterized by unexplained ventricular myocardial hypertrophy and risk of heart failure and sudden death. FHOD3 encodes a cardiac formin that nucleates and bundles actin filaments in sarcomeres, suggesting a mechanistic link to HCM pathogenesis. Initial case–control sequencing studies and familial analyses implicate diverse FHOD3 variants in HCM across multiple populations.

In a cohort of 3,189 unrelated HCM probands versus 2,777 controls, protein‐altering FHOD3 variants were enriched in patients (74/3,189 vs 18/2,777; p < 0.001) and clustered in a conserved coiled‐coil domain (amino acids 622–655) with an odds ratio of 21.8 compared with disease controls (PMID:30442288). Subsequent analysis of 1,000 HCM patients and 761 controls identified 27 FHOD3 candidate variants in 33 (3.3%) patients versus 12 controls (1.6%; OR 2.13; P < 0.05), including a splice‐donor truncating variant c.1286+2delT that segregated in four affected relatives (PMID:33586461).

Copy‐number variant analysis in 5,493 HCM probands detected three symmetrical deletions of FHOD3 exons 15–16 in affected families but none in 2,973 controls, reinforcing the relevance of loss‐of‐function alleles in HCM (PMID:32335906). A founder splice‐site variant c.1646+2T>C was found in eight probands and seven relatives in the Balkans, accounting for 16% of FHOD3‐related HCM in that cohort (PMID:38051749). Moreover, the intermediate‐effect missense variant p.Arg637Gln (c.1910G>A) was enriched in 284 of 9,668 HCM probands (2.94%) versus 64 of 11,480 internal controls (0.59%; OR 5.40; 95% CI 4.11–7.09) and associated with severe, early‐onset HCM in homozygous carriers (PMID:38160043).

Segregation analysis across 17 unrelated families yielded a combined LOD score of 7.92, with the p.Ser527del (c.1580_1582del (p.Ser527del)) variant detected in all affected members and absent in unaffected relatives except one young individual (PMID:31742804). The FHOD3‐variant spectrum includes at least 25 missense, two truncating, splice‐site, and exon‐level deletions, indicating diverse mutational mechanisms.

Functional studies confirm that muscle isoforms of FHOD3 localize to myofibrils via CK2 and ROCK1 phosphorylation, promoting actin filament assembly in cardiomyocytes (PMID:23052206). Fhod3 interacts directly with cardiac myosin‐binding protein C to target the C‐zone of sarcomeres, and its mislocalization exacerbates cardiomyopathy phenotypes in cMyBP‐C‐null mice (PMID:29686099). Early work demonstrated Fhos2’s actin‐organizing activity and intermediate filament association in cardiac cells (PMID:15966898).

Integration of extensive case–control data, familial segregation, founder and intermediate‐effect variants, and concordant functional assays supports a strong, autosomal dominant association between FHOD3 and HCM. Additional GWAS‐linked loci and CNV findings further substantiate its role. Key Take-home: FHOD3 should be included in HCM genetic testing panels for diagnostic decision-making and risk stratification.

References

• Journal of the American College of Cardiology • 2018 • Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy. PMID:30442288
• Journal of the American Heart Association • 2021 • Variant Spectrum of Formin Homology 2 Domain-Containing 3 Gene in Chinese Patients With Hypertrophic Cardiomyopathy. PMID:33586461
• Clinical Genetics • 2020 • Deletions of specific exons of FHOD3 detected by next-generation sequencing are associated with hypertrophic cardiomyopathy. PMID:32335906
• PLoS One • 2023 • A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans-A cohort study. PMID:38051749
• Journal of Medical Genetics • 2024 • Intermediate-effect size p.Arg637Gln in FHOD3 increases risk of HCM and is associated with an aggressive phenotype in homozygous carriers. PMID:38160043
• Genes to Cells • 2005 • Fhos2, a novel formin-related actin-organizing protein, probably associates with the nestin intermediate filament. PMID:15966898
• Cellular and Molecular Life Sciences • 2013 • Two distinct phosphorylation events govern the function of muscle FHOD3. PMID:23052206
• Proceedings of the National Academy of Sciences of the United States of America • 2018 • Interaction between cardiac myosin-binding protein C and formin Fhod3. PMID:29686099

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