Clinical spectrum, cardiac phenotypes, and outcomes of FHL1-related cardiomyopathies: a systematic review

Clinical Snapshot

Key Findings

• P Value: Not reported; no formal statistical testing performed

• Effect Size: Left ventricular hypertrophy in 56% of patients; arrhythmias in 51%; skeletal muscle involvement in 75%; conduction abnormalities in 8%

• Primary Outcome: Characterisation of cardiac and neuromuscular phenotype in 114 patients with pathogenic/likely pathogenic FHL1 mutations across 22 studies

• Nnt Or Sensitivity: Sudden cardiac death incidence 7%; heart transplantation rate 5%; median age of onset 18 years (IQR 10–26); male sex 69% of cohort. No NNT, sensitivity, specificity, or hazard ratio calculable from available data.

• Confidence Interval: Not reported; no confidence intervals provided for any outcome proportion

Clinical Application

FHL1 genetic testing is technically feasible via next-generation sequencing gene panels for inherited cardiomyopathies. Clinical integration requires multidisciplinary input from cardiologists, clinical geneticists, and neuromuscular specialists. Variant interpretation requires access to ClinVar, ACMG classification frameworks, and ideally functional studies for variants of uncertain significance. In Australia, FHL1 is not currently a standalone PBS-listed genetic test; however, FHL1 is included in comprehensive inherited cardiomyopathy and neuromuscular gene panels available through state-based genetic services and private laboratories (e.g., Victorian Clinical Genetics Services, Genomics for Life). The RACGP and CSANZ guidelines on inherited cardiac conditions support genetic testing in index cases with unexplained cardiomyopathy and family history screening. TGA-approved ICD devices are available for primary prevention in high-risk patients. Cardiac genetic clinics at major Australian centres (e.g., Royal Melbourne Hospital, St Vincent's Sydney, Royal Brisbane) are equipped to manage such cases. The rarity of FHL1-related disease means Australian prevalence data are absent; national rare disease registries (e.g., ANZCTR-linked cohorts) may be relevant for future data collection. Young patients (adolescents and young adults) presenting with unexplained left ventricular hypertrophy, particularly when accompanied by skeletal myopathy, elevated creatine kinase, contractures, or a family history of early cardiac disease or sudden death. Male patients with X-linked inheritance patterns warrant heightened suspicion.

Abstract

BACKGROUND: Mutations in the Four-and-a-Half LIM Domains 1 (FHL1) gene are increasingly recognized as a rare cause of inherited cardiomyopathies, often associated with skeletal myopathy and adverse cardiac outcomes. The phenotypic spectrum and clinical implications of FHL1 variants remain poorly defined. OBJECTIVE: To systematically review published cases of FHL1-related cardiomyopathy and characterize the clinical, genetic, and pathological features. METHODS: We conducted a systematic literature search in PubMed and EMBASE up to July 2025 using predefined criteria to identify studies reporting clinical cases of patients with FHL1 mutations and cardiac involvement. Data on genotype, phenotype, cardiac and neuromuscular features, and clinical outcomes were extracted and synthesized. RESULTS: Twenty-two studies were included, comprising 114 patients with pathogenic or likely pathogenic FHL1 mutations. Most patients were male (69%), with a median age of onset of 18 (IQR 10-26) years. Cardiac involvement consisted in left ventricular hypertrophy (56%), followed by arrhythmias (51%), and conduction abnormalities (8%). The incidence of sudden cardiac death was 7%, and heart transplantation was reported in 5% of patients. Skeletal muscle involvement was present in 75%, ranging from mild contractures to more severe myopathic phenotypes with functional impairment. Creatine kinase levels were variably elevated. Truncating variants were reported in several severe cardiac presentations in young males, while isolated cardiac disease occurred with selected variants. CONCLUSIONS: FHL1-related cardiomyopathy is a rare but important diagnosis. Genetic testing should be considered in patients with cardiac hypertrophy and neuromuscular features. Further research is needed to define prognostic markers and guide management.

References

1. 1.Bobbio, E., Caiazza, M., Pisacane, F., Viscovo, I., Gentile, A., Monda, E., De Falco, C., Esposito, D., Borrelli, F., Losi, M., Bossone, E., Chen, S. N., Frisso, G., Calabrò, P., Esposito, G., Lombardi, R., & Limongelli, G. (2026). Clinical spectrum, cardiac phenotypes, and outcomes of FHL1-related cardiomyopathies: a systematic review. BMC Cardiovascular Disorders. PubMed ID: 42304238.