RBM20 is a muscle-specific RNA-binding protein that functions as a splicing regulator essential for cardiac function 1. It acts as a repressor of mRNA splicing by binding the 5'UCUU-3' motif in intronic sequences, leading to exon skipping in target genes including TTN (titin), CACNA1C, CAMK2D, and PDLIM5 2. RBM20-mediated splicing is critical for titin isoform transitions that regulate ventricular filling and cardiac adaptive responses 2. Beyond titin regulation, RBM20 coordinates splicing of ~30 conserved genes enriched for cardiomyopathy-linked, ion-handling, and sarcomere proteins 2. Pathogenic RBM20 variants cause aggressive dilated cardiomyopathy (DCM) with early-onset heart failure and high mortality 1. RBM20 mutations demonstrate definitive evidence for monogenic DCM 3. Disease mechanisms involve both disrupted splicing and protein mislocalization: variants in the arginine-serine-rich domain cause nuclear export defects and aberrant cytoplasmic ribonucleoprotein granule formation 4. Notably, RBM20 mutation carriers exhibit increased ventricular arrhythmia risk (44% vs. 5% in TTN carriers) 5, linked to aberrant CAMK2D splicing causing calcium overload and spontaneous sarcoplasmic reticulum calcium releases 5. Recent therapeutic advances include adenine base editing and prime editing strategies that successfully correct pathogenic mutations, restore nuclear localization, normalize splicing, and extend lifespan in disease models 4.