RBM20 Truncating Variants in Dilated Cardiomyopathy: Reduced Penetrance and Milder Phenotype Compared to Missense Variants

Highlights

1. RBM20 truncating variants (RBM20tvs) contribute to arrhythmogenic dilated cardiomyopathy but with reduced lifetime penetrance compared to titin truncating variants (TTNtvs).

2. Patients with RBM20tvs present later in life and have less family history of sudden cardiac arrest or cardiomyopathy compared to those with pathogenic missense variants.

3. The study provides crucial insights for genetic counseling and clinical management of patients with RBM20 variants.

Background

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and sudden cardiac death, with genetic variants playing a significant role in its etiology. Pathogenic or likely pathogenic (P/LP) missense variants in the RBM20 gene are known to cause a highly penetrant arrhythmogenic DCM. However, the clinical significance of RBM20 truncating variants (RBM20tvs) remains unclear. This study aims to elucidate the role of RBM20tvs in arrhythmogenic DCM by comparing their clinical impact with P/LP RBM20 missense variants and TTNtvs.

Study Design

This cohort study utilized data from the genome-first UK Biobank (UKB) and All of Us populations to assess the etiologic fraction, natural history, and penetrance of RBM20 variants. Retrospective data were also collected from an international cohort of patients with DCM and RBM20 variants identified at centers of excellence for genetic heart disease. The study compared RBM20 variants with known P/LP variants and variants of uncertain significance in RBM20, as well as TTNtvs. The primary outcomes measured were major ventricular arrhythmias, end-stage heart failure, and heart failure hospitalization.

Key Findings

The study included two main cohorts: the UK Biobank cohort with 4,249 participants (44% male) and the RBM20 registry with 179 patients (58.6% male). A validation cohort from the All of Us biobank consisted of 7,002 participants (62% male). The etiologic fraction of RBM20 variants in arrhythmogenic DCM was 0.53 (95% CI, 0.32-0.67; P < .001). Patients with RBM20tvs and DCM presented to referral centers later in life (mean age 53 vs. 34 years) and were less likely to have a family history of sudden cardiac arrest (20% vs. 65%) or cardiomyopathy (20% vs. 78%) compared to those with P/LP RBM20 variants. There was no significant difference in age- and sex-adjusted incident major heart failure or arrhythmia events between the groups, though the lifetime hazard was reduced in those with RBM20tvs (hazard ratio, 0.13; 95% CI, 0.03-0.56; P = .01).

Expert Commentary

The findings underscore the importance of genetic testing and counseling for patients with DCM, particularly those with RBM20 variants. While RBM20tvs confer a milder phenotype compared to P/LP variants, their potential for additive interactions with other damaging variants should not be overlooked. The study’s limitations include its retrospective design and reliance on diagnostic codes in the UK Biobank, which may underestimate true disease prevalence.

Conclusion

This study demonstrates that RBM20tvs contribute to arrhythmogenic DCM but with reduced penetrance and milder clinical severity compared to P/LP missense variants and TTNtvs. These findings have significant implications for risk stratification and family screening in DCM patients. Future research should explore the mechanistic basis of these phenotypic differences and the potential for targeted therapies.

Funding and ClinicalTrials.gov

The study did not disclose specific funding sources or ClinicalTrials.gov registration numbers due to institutional review board restrictions.

References

1. Floyd BJ, et al. RBM20 Truncating Variants and Human Cardiomyopathy. JAMA Cardiology. 2026; PMID: 41949880.