Pathogenic FHL1 mutations are associated with a high prevalence of cardiac involvement, most commonly left ventricular hypertrophy (56%) and abnormal electrocardiograms (51%), alongside skeletal muscle abnormalities (75%).
Systematic Review (n=114)
FHL1-related cardiomyopathy is a rare condition predominantly affecting young males, characterized by left ventricular hypertrophy, arrhythmias, and skeletal muscle involvement, with notable risks of sudden cardiac death and heart transplantation.
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.
Bobbio et al. (Wed,) conducted a systematic review in FHL1-related cardiomyopathies (n=114). FHL1 mutations was evaluated on Left ventricular hypertrophy. Pathogenic FHL1 mutations are associated with a high prevalence of cardiac involvement, most commonly left ventricular hypertrophy (56%) and abnormal electrocardiograms (51%), alongside skeletal muscle abnormalities (75%).