Cohort analysis of variants in the RBM20 gene. Is there a profile for electrocardiographic phenotype, arrhythmogenic features and outcomes?

Background The RBM20 gene encodes a protein involved in RNA splicing regulation. First linked to cardiomyopathy in 2009, its prevalence according to the recent 2023 cardiomyopathy classification, in each proposed phenotype remains uncertain. Purpose To describe the phenotypic profile of carriers of pathogenic/likely pathogenic RBM20 variants. Methods This ambispective, observational cohort study in patients with pathogenic/likely pathogenic RBM20 variants identified through genetic testing for structural heart disease or high-risk arrhythmogenic phenotypes (aborted sudden cardiac death (SCD) or sustained ventricular arrhythmias) without structural heart disease and with a family history (FH) of suspected SCD. Data collected between April 2021 and December 2023, included clinical features, diagnostic findings, and severe outcomes such as life-threatening arrhythmic events (sustained VT, SCD, ICD therapies), end-stage heart failure, or heart transplantation (Htx). Results Fourteen patients (12 probands, mean age 41 years, 57.1% male) were included. At presentation, 5/14 (35.7%) were asymptomatic, 8/14 (57.1%) had heart failure symptoms. ECG had a mean PR interval of 140 ms, with 5/14 (35.7%) <120 ms, and a mean QRS of 101.6 ms. None had low QRS voltage. DCM was diagnosed in 9/14 (64.3%), high-risk arrhythmogenic phenotype in 3/14 (21.4%), isolated left ventricular dilatation (iLVD) in 1/14 (7.1%), and familial screening with a negative phenotype in 1/14 (7.1%). In the DCM group, the mean LVEF was 27%, with mild late gadolinium enhancement in 4/9 (44.4%). Severe outcomes were only seen in the DCM group, such as Htx in 1/9 (11.1%) and SCD in 2/9 (22.2%), both with mild hypertrophy on histological evaluation. In the high-risk arrhythmogenic phenotype, the mean LVEF was 61.7%. Two patients exhibited sustained polymorphic VT during stress testing (ST), combined with a FH of DCM/SCD, and one had an aborted SCD. One was classified as iLVD, with LGE and non-sustained polymorphic VT during ST. Six distinct variants were identified, with p.Arg634Trp being the most common. Conclusion RBM20-related cardiomyopathy spans a broad phenotypic spectrum, from preserved ejection fraction with arrhythmias to end-stage heart failure and low incidence of LGE at cardiac resonance. Typical features include normal or short PR intervals and narrow QRS complexes. Expanding genotype-phenotype correlations is crucial to refining age-dependent penetrance, optimizing care for patients and their families.