RBM20 Truncating Variants Show Low Penetrance in Arrhythmogenic Dilated Cardiomyopathy

RBM20 truncating variants (RBM20tvs) appear to contribute to arrhythmogenic dilated cardiomyopathy (DCM) but with substantially lower disease penetrance and milder clinical severity than other well-established genetic causes, according to a new cohort study published in JAMA Cardiology.¹

Study Evaluates Genetic Contribution of RBM20 Variants

Researchers sought to clarify the role of RBM20tvs in arrhythmogenic DCM by analyzing data from large population biobanks and a clinical registry of genetically confirmed patients with DCM. The study included 4249 participants from the UK Biobank, 7002 participants from the All of Us Research Program, and 179 patients from an international RBM20 registry.

The primary objective was to compare RBM20tvs with pathogenic or likely pathogenic RBM20 missense variants and titin truncating variants (TTNtvs), which are among the most common genetic causes of DCM.

RBM20 Variants Show Lower Disease Penetrance

Across genome-first biobanks, investigators found that RBM20 variants were associated with a lower lifetime incidence of cardiomyopathy, heart failure, or major ventricular arrhythmias compared with TTNtvs. The HR was 0.55 (95% CI, 0.36-0.84; P < .001), indicating a significantly reduced risk.

The etiologic fraction of RBM20 variants in arrhythmogenic DCM was estimated at 0.53 (95% CI, 0.32-0.67; P < .001), suggesting a moderate but not dominant contribution to disease development at the population level.

Milder Clinical Course in RBM20 Truncating Variant Carriers

Patients with RBM20tvs who developed DCM showed a notably milder clinical course than those carrying pathogenic RBM20 variants. Individuals with RBM20tvs presented later in life, at a mean (SD) age of 53 (10) years compared with 34 (18) years in those with pathogenic RBM20 variants.

In addition, RBM20tvs carriers were less likely to have a family history of sudden cardiac arrest (20% vs 65%) or cardiomyopathy (20% vs 78%), suggesting reduced familial clustering and penetrance.

Although age- and sex-adjusted analyses showed no significant difference in incident heart failure or arrhythmia events between RBM20tv carriers and those with pathogenic RBM20 variants, lifetime hazard was significantly reduced in the RBM20tv group (HR, 0.13; 95% CI, 0.03-0.56; P = .01).

Furthermore, when compared with TTNtvs, RBM20 variants were associated with significantly fewer lifetime cardiovascular events. This supports the notion that RBM20tvs confer a comparatively lower genetic risk burden.

Clinical Implications for Genetic Cardiomyopathy

The findings suggest that RBM20 truncating variants should be considered low-effect contributors to arrhythmogenic DCM rather than highly penetrant disease-causing mutations. However, the authors emphasized that RBM20 variants may still interact with other genetic abnormalities to influence disease expression. These results may help refine risk stratification in inherited cardiomyopathy and improve the interpretation of genetic testing results in clinical practice.

DCM is recognized as a major public health issue and is the most common form of cardiomyopathy in adults and children.² It is a leading cause of non-ischemic heart failure and the primary indication for heart transplantation.

Overall, RBM20 truncating variants appear to contribute to dilated cardiomyopathy but with lower penetrance and milder disease expression than other pathogenic variants.¹ These findings may help clinicians better interpret genetic testing results and guide more individualized management of inherited cardiomyopathy.

“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,” the researchers wrote. “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. Wettrell G. Dilated cardiomyopathy of unknown cause in young patients: risk evaluation, possible etiologies, and treatment. Libyan J Med. 2007;2(4):157-8. doi:10.4176/070915