Key result
RBM20 truncating variants are linked to ~22-point lower 5-year adverse composite events vs missense variants.
Why the study?
Pathogenic RBM20 missense variants are associated with an aggressive cardiomyopathy phenotype, whereas data on RBM20 truncating variants are limited and contradictory.
Does carrying RBM20 truncating variants confer a lower risk of malignant ventricular arrhythmia and end-stage heart failure compared to carrying pathogenic or likely pathogenic RBM20 missense variants?
Cohort (n=163)
Yes
Does carrying RBM20 truncating variants confer a lower risk of malignant ventricular arrhythmia and end-stage heart failure compared to carrying pathogenic or likely pathogenic RBM20 missense variants?
Carriers of RBM20 truncating variants experienced significantly lower rates of heart failure admissions, end-stage heart failure, and malignant ventricular arrhythmias compared to missense variant carriers, indicating a need for variant-specific risk stratification.
May support variant-specific risk stratification in RBM20 cardiomyopathy; hypothesis-generating and requires prospective validation.
Background Pathogenic missense variants in RBM20 (RBM20mv) are associated with an aggressive cardiomyopathy phenotype characterised by high rates of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF).1 Data on RBM20 truncating variants (RBM20tv) are limited and contradictory.2,3 Purpose To compare the phenotype and clinical outcomes of individuals carrying pathogenic or likely pathogenic (P/LP) RBM20mv and RBM20tv. Methods Consecutive RBM20tv and P/LP RBM20mv carriers were retrospectively recruited from 12 international centres. Baseline characteristics and clinical outcomes were compared. Survival analysis was performed at 5 years of follow-up for a composite endpoint of MVA (sudden cardiac death, appropriate implantable cardioverter defibrillator therapy or sustained ventricular arrhythmia) or ESHF (left ventricular assist device implantation, heart transplant or heart failure death). Results Among 163 RBM20 variant carriers (143 RBM20mv and 20 RBM20tv) with a median follow-up of 78 months, 102/143 (71%) RBM20mv and 10/20 (50%) RBM20tv carriers met diagnostic criteria for dilated cardiomyopathy by the end of follow-up (p=0.1). Heart failure admissions occurred in 30/143 (21%) RBM20mv and 0/20 RBM20tv carriers (p=0.03). 3/20 (15%) RBM20tv and 7/143 (5%) RBM20mv had MVA either prior to or at baseline (p = 0.1) and were excluded from survival analysis. At 5 years of follow-up, thirty of 153 RBM20 variant-carriers had the primary composite endpoint (30/136 (22.1%) RBM20mv carriers versus 0/17 RBM20tv carriers, log rank p value = 0.05). Conclusion RBM20tv carriers had no heart failure admissions during follow-up and no ESHF or MVA at 5 years. These findings support the hypothesis that disease mechanisms differ between RBM20mv and RBM20tv and that caution should be used in applying the same approach to risk stratification.
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Cannie et al. (2026) conducted a cohort in RBM20 variant-associated cardiomyopathy (n=163). RBM20 truncating variants (RBM20tv) vs. Pathogenic/likely pathogenic RBM20 missense variants (RBM20mv) was evaluated on Composite of malignant ventricular arrhythmia (sudden cardiac death, appropriate ICD therapy or sustained ventricular arrhythmia) or end-stage heart failure (LVAD implantation, heart transplant or heart failure death) at 5 years (p=0.05). RBM20 truncating variants were associated with a lower 5-year rate of malignant ventricular arrhythmia or end-stage heart failure vs missense variants (0% vs 22.1%, log-rank p=0.05).
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