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The contribution of RBM20 truncating variants to human cardiomyopathy

Brendan J Floyd, Joyce N Njoroge, Vikki A Krysov

    Medrxiv : the Preprint Server for Health Sciences
    |August 8, 2025
    PubMed

    Insights

    Truncating variants in RBM20 (RBM20tvs) contribute to arrhythmogenic dilated cardiomyopathy (DCM) but cause milder disease. These RBM20tvs show reduced lifetime disease penetrance compared to other truncating variants.

    Area of Science:

    • Cardiovascular Genetics
    • Molecular Cardiology
    • Genetic Etiology of Cardiomyopathies

    Background:

    • Dilated cardiomyopathy (DCM) diagnosis increasingly relies on genetic testing.
    • Missense variants in RBM20 are known to cause highly penetrant arrhythmogenic DCM.
    • The clinical significance of truncating RBM20 variants (RBM20tvs) in DCM remains unclear.

    Purpose of the Study:

    • To assess the contribution of RBM20tvs to the development of DCM.
    • To evaluate the natural history and penetrance of RBM20tvs in an international cohort.
    • To compare RBM20tvs DCM with RBM20 missense variants and other truncating variants.

    Main Methods:

    • Assembled an international cohort of DCM patients with RBM20 variants.
    • Utilized genome-first UK Biobank data for analysis.
    • Assessed etiologic fraction, natural history, and penetrance of RBM20tvs.

    Main Results:

    • RBM20tvs had a modest etiologic fraction in arrhythmogenic DCM.
    • Patients with RBM20tvs DCM presented later and had less family history of cardiac events compared to RBM20 missense variant carriers.
    • No significant difference in major heart failure or arrhythmia events, but reduced lifetime hazard in RBM20tvs DCM.
    • Lower incidence of cardiomyopathy, heart failure, or major ventricular arrhythmia in UK Biobank participants with RBM20tvs versus T-box transcription factor T (TTNtvs).

    Conclusions:

    • RBM20tvs contribute to arrhythmogenic DCM phenotypes.
    • RBM20tvs confer milder disease severity and reduced lifetime penetrance compared to RBM20 missense variants.
    • Consider potential additive interactions of RBM20tvs with other variants in DCM patients and families.
    Abstract

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