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

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

Journal: BMC cardiovascular disorders 2026;26(1):

PMID: 42304238

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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.

Address: Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania 'Luigi Vanvitelli', Monaldi Hospital, via Leonardo Bianchi 1, Naples, 80131, Italy. [email protected].; Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden. [email protected].; Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. [email protected].; Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania 'Luigi Vanvitelli', Monaldi Hospital, via Leonardo Bianchi 1, Naples, 80131, Italy.; Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania 'Luigi Vanvitelli', Monaldi Hospital, via Leonardo Bianchi 1, Naples, 80131, Italy.; UOC Patologia Clinica, AORN dei Colli, via Leonardo Bianchi 1, Naples, 80131, Italy.; Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini 5, Naples, 80131, Italy.; Division of Cardiology, University of Colorado School of Medicine, 12505 E. 16th Avenue, Anschutz Inpatient Pavilion 2, Aurora, CO, 80045, USA.; Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini 5, Naples, 80131, Italy.; Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, Gothenburg, Sweden.; Department of Endocrinology at Sahlgrenska University Hospital, University of Gothenburg, Blå Stråket 8, Gothenburg, 413 45, Sweden.; Department of Public Health, University of Naples Federico II, Via Pansini 5, Naples, 80131, Italy.; Heart Centre of Excellence, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.; Division of Cardiology, University of Colorado School of Medicine, 12505 E. 16th Avenue, Anschutz Inpatient Pavilion 2, Aurora, CO, 80045, USA.; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, Naples, 80131, Italy.; Department of Translational Medical Sciences, University of Campania Luigi Vanvitelli, Caserta, 81100, Italy.; Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania 'Luigi Vanvitelli', Monaldi Hospital, via Leonardo Bianchi 1, Naples, 80131, Italy.; Department of Translational Medical Sciences, University of Campania Luigi Vanvitelli, Caserta, 81100, Italy.; Institute of Cardiovascular Science, University College London, Gower Street, London, WC1E 6BT, UK.

DOI: 10.1186/s12872-026-06096-x

MeSH Terms: Humans, Muscle Proteins, Phenotype, LIM Domain Proteins, Intracellular Signaling Peptides and Proteins, Genetic Predisposition to Disease, Mutation, Male, Cardiomyopathies, Female, Risk Factors, Adolescent, Adult, Young Adult, Child, Prognosis, Risk Assessment, Death, Sudden, Cardiac, Middle Aged