Background: RNA-binding motif protein 20 (RBM20) regulates post-transcriptional splicing, particularly in sarcomeric, but also in other cardiac genes crucial for homeostasis. RBM20 variants are a rare cause of cardiomyopathy (CMP), but genotype-phenotype correlation is still elusive, starting from the type of CMP (dilated, non-compacted, hypertrophic, and even restrictive phenotypes have been described), and ranging to sex-dependent and arrhythmic expression.
Purpose: To describe cardiac involvement in 8 patients with RBM20 variants.
Methods: 189 patients (pts) underwent genetic analysis in our center (2019–2022) for suspected genetic CMP (TruSight Cardio panel, Illumina); 72% had a positive genetic report, including pathogenic/likely pathogenic (P/LP) or variants of undetermined significance (VUS). Among them, 9 (5%, 6 males and 3 females, from 6 families) carried a heterozygous RBM20 variant: 5 a sole P variant, 3 an RBM20-VUS associated to a second VUS in another CMP related gene, one an RBM20-VUS associated to a LP variant in BAG3; the last patient was excluded (figure with 8 pts).
Results: Most pts (75%) had a positive family history (FH) for sudden death. Mean age at diagnosis was significantly lower for P variant carriers compared to VUS carriers (25±15 vs 46±2 years, p=0.04); no other significant differences were found between the 2 groups. At diagnosis, 4/8 pts (50%) had NYHA class>2, mean LVEF was 34±18% and mean LV end diastolic volume 83±14 ml/m2; most pts (6/8, 75%) presented with a dilated phenotype, one with a non-compacted and one with a hypertrophic phenotype. Cardiac magnetic resonance, available in 6 pts, showed non-ischemic fibrosis in 3 (50%). At presentation, two pts had non-sustained VT (NSVT), one atrial flutter, one first degree AV block. The median follow-up was 2 years (IQR 2-10). Four pts (50%) underwent ICD implantation at 40 ± 13 years old. One female patient underwent heart transplant at the age of 13 and no one died from end stage HF; 3 pts had NSVT, one patient had atrial fibrillation (successfully treated with ablation), and none developed advanced AV blocks.
Conclusions: This is the first Italian case series of RMB20 variants related CMP. In our case series, RBM20 variants are associated with an early onset cardiac expression both in male and female pts, with LV dilated CMP and heart failure being the most common presentation. None of the pts presented with or developed advanced AV blocks, most suffered from NSVT.