RBM20 Genetic Variants Linked to Arrhythmogenic Dilated Cardiomyopathy

Genetic testing is playing an increasingly central role in the management of dilated cardiomyopathy (DCM), helping clinicians refine prognosis, guide surveillance, and inform family screening.¹ New research published in JAMA Cardiology demonstrates that variants in the RBM20 gene are associated with arrhythmogenic forms of DCM, but with distinct differences in disease severity and lifetime risk depending on the variant type.

“This cohort study set out to evaluate potential disease contributions and relative severity of DCM associated with classes of variants like RBM20 variants,” wrote the researchers of the study. “Understanding such contributions will expand the utility of genetic testing for patients with DCM.”

RBM20 has previously been implicated in highly penetrant, arrhythmogenic DCM when pathogenic or likely pathogenic (P/LP) missense variants are present. However, the clinical significance of RBM20 truncating variants (RBM20tvs) has remained unclear. This study sought to clarify their role by comparing outcomes across variant types, including RBM20tvs, P/LP RBM20 variants, and titin truncating variants (TTNtvs), a well-established genetic driver of DCM.

Investigators evaluated the contribution of RBM20 variants to arrhythmogenic DCM using a combination of genome-first population data and retrospective clinical cohorts. Data were drawn from the UK Biobank and the All of Us Research Program, alongside an international registry of patients with DCM and RBM20 variants identified at specialized genetic heart disease centers.

Across the UK Biobank cohort of 4249 participants and the All of Us validation cohort of 7002 individuals, RBM20 variants were found to contribute meaningfully to arrhythmogenic DCM, with an etiologic fraction of 0.53 (95% CI, 0.32-0.67; P < .001). However, the lifetime incidence of cardiomyopathy, heart failure (HF), or major ventricular arrhythmias was significantly lower among individuals with RBM20 variants compared with those carrying TTNtvs (HR, 0.55; 95% CI, 0.36-0.84; P < .001).

Findings from the international RBM20 registry further highlighted important clinical distinctions. Patients with RBM20 truncating variants presented later in life than those with P/LP RBM20 variants, with a mean (SD) age of 53 (10) years compared with 34 (18) years (P < .001). They were also less likely to report a family history of sudden cardiac arrest or cardiomyopathy, suggesting lower familial penetrance.

Despite these differences, the study found no significant variation in age- and sex-adjusted rates of major HF or arrhythmic events between patients with RBM20tvs and those with P/LP RBM20 variants once DCM was established. However, lifetime risk remained lower among RBM20tv carriers (HR, 0.13; 95% CI, 0.03-0.56; P = .01), reinforcing the notion of a milder disease trajectory overall.

Prior research suggests that RBM20-related cardiomyopathy has historically been associated with more severe, highly arrhythmogenic disease, including substantial risks of ventricular arrhythmias and HF progression.² This contrast highlights the significance of the current findings, which refine understanding by showing that truncating RBM20 variants may confer a comparatively milder and lower-penetrance phenotype than previously recognized.

This study has key limitations, including potential selection bias from tertiary care cohorts that may overrepresent more severe disease. Although genome-first datasets help offset this, reliance on diagnostic codes may underestimate the true effect of RBM20 variants. Additionally, the small sample size of patients with RBM20 truncating variants underscores the need for larger collaborative studies in rare disease.

Overall, the study finds that RBM20 variants contribute to arrhythmogenic dilated cardiomyopathy but demonstrate lower penetrance and generally milder disease than TTN truncating and pathogenic RBM20 variants, highlighting the importance of variant-specific interpretation in clinical care.

“This study found that RBM20 variants contributed to arrhythmogenic DCM phenotypes but conferred reduced lifetime disease penetrance compared to TTNtvs and milder disease severity alone than P/LP RBM20 variants,” wrote the researchers. “Their potential for additive interactions with other damaging variants should be considered in patients with DCM and their families.”

References

1. Floyd BJ, Njoroge JN, Krysov VA, et al. RBM20 truncating variants and human cardiomyopathy. JAMA Cardiol. Published online April 08, 2026. doi:10.1001/jamacardio.2026.0401

2. Martini M, Bueno Marinas M, Rigato I, et al. Clinical insights in RNA-binding protein motif 20 cardiomyopathy: a systematic review. Biomolecules. 2024;14(6):702. doi:10.3390/biom14060702