The contribution of RBM20 truncating variants to human cardiomyopathy

BackgroundGenetic diagnosis has become increasingly important to guide clinical decision making for patients with dilated cardiomyopathy (DCM). Disease-causing (P/LP) missense variants in the gene RBM20 cause a highly penetrant arrhythmogenic dilated cardiomyopathy (DCM), but the role of truncating RBM20 variants (RBM20tvs) is unclear. ObjectiveAssess the contribution of RBM20tvs to DCM. MethodsWe assembled an international cohort of DCM patients with RBM20 variants and used data from the genome-first UK Biobank (UKB) to assess the etiologic fraction, natural history and penetrance of RBM20tvs. ResultsThe etiologic fraction of RBM20tvs in arrhythmogenic DCM was modest (0.53[0.32,0.67], p=7.5x10-5). RBM20tv DCM patients presented to referral centers later in life than RBM20 P/LP DCM patients (53{+/-}10 vs. 34{+/-}18 years, p=4x10-3), and were less likely to have a family history of sudden cardiac arrest (20% vs. 65%, p= 0.046) or cardiomyopathy (20% vs. 78% p=5.4x10-3). There was no significant difference in age- and sex-adjusted incident major heart failure or arrhythmia events between RBM20tv and RBM20 P/LP DCM patients, though sex-adjusted lifetime hazard was reduced in RBM20tv DCM (HR 0.15[0.03,0.66],p=0.009). In UKB, lifetime incidence of cardiomyopathy, heart failure, or major ventricular arrhythmia diagnosis was lower in participants with RBM20tvs than in those with TTNtvs (HR 0.55 [0.36,0.84], p=5.9x10-3). ConclusionsRBM20tvs contribute to arrhythmogenic DCM phenotypes, but confer milder disease severity alone than RBM20 P/LP variants, and reduced lifetime disease penetrance compared to TTNtvs. Their potential for additive interactions with other damaging variants should be considered in DCM patients and families.