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Background <p>Mutations in the <i>Four-and-a-Half LIM Domains 1</i> (<i>FHL1</i>) 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 <i>FHL1</i> variants remain poorly defined.</p> Objective <p>To systematically review published cases of <i>FHL1</i>-related cardiomyopathy and characterize the clinical, genetic, and pathological features.</p> Methods <p>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 <i>FHL1</i> mutations and cardiac involvement. Data on genotype, phenotype, cardiac and neuromuscular features, and clinical outcomes were extracted and synthesized.</p> Results <p>Twenty-two studies were included, comprising 114 patients with pathogenic or likely pathogenic <i>FHL1</i> 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.</p> Conclusions <p><i>FHL1</i>-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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月17日

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  • Emanuele Bobbio,
  • Martina Caiazza,
  • Filomena Pisacane,
  • Immacolata Viscovo,
  • Alessandro Gentile,
  • Emanuele Monda,
  • Chiara De Falco,
  • Daniela Esposito,
  • Felice Borrelli,
  • Mariangela Losi,
  • Eduardo Bossone,
  • Suet Nee Chen,
  • Giulia Frisso,
  • Paolo Calabrò,
  • Giovanni Esposito,
  • Raffaella Lombardi,
  • Giuseppe Limongelli

摘要

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.