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RBM20 Truncating Variants and Human Cardiomyopathy
Brendan J Floyd1, Joyce N Njoroge1, Vikki A Krysov1
1Stanford Center for Inherited Cardiovascular Disease and Department of Medicine, Stanford School of Medicine, Stanford, California.
JAMA Cardiology
|April 8, 2026
Summary
RBM20 truncating variants contribute to arrhythmogenic dilated cardiomyopathy (DCM) but show reduced disease penetrance compared to titin truncating variants. These RBM20 variants may indicate milder disease severity, warranting consideration for genetic counseling in DCM families.
Area of Science:
- Cardiovascular Genetics
- Genetic Cardiology
- Molecular Cardiology
Background:
- Genetic diagnosis is crucial for dilated cardiomyopathy (DCM) management.
- RBM20 missense variants cause highly penetrant arrhythmogenic DCM.
- The role of RBM20 truncating variants (RBM20tvs) in DCM remains unclear.
Purpose of the Study:
- To determine the contribution of RBM20 variants to arrhythmogenic DCM.
- To evaluate the penetrance and natural history of RBM20 variants.
Main Methods:
- Cohort study utilizing UK Biobank and All of Us populations.
- Retrospective analysis of an international DCM cohort with RBM20 variants.
- Comparison of RBM20 variants with known pathogenic variants and titin truncating variants (TTNtvs).
Main Results:
- RBM20 variants accounted for 0.53 etiologic fraction in arrhythmogenic DCM.
- Lifetime incidence of cardiomyopathy or major ventricular arrhythmia was lower in participants with RBM20 variants versus TTNtvs.
- Patients with RBM20tvs and DCM presented later and had less family history of sudden cardiac arrest or cardiomyopathy compared to P/LP RBM20 variants.
Conclusions:
- RBM20 variants contribute to arrhythmogenic DCM phenotypes.
- RBM20tvs confer reduced lifetime disease penetrance and milder severity than P/LP RBM20 variants.
- Consideration of RBM20 variants' potential for additive interactions with other damaging variants is important for DCM families.
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