Abstract

BACKGROUND: Patients with RBM20 cardiomyopathy present with an aggressive phenotype, associated with premature malignant arrhythmias, sudden cardiac death, and progressive heart failure (HF). This study aimed to investigate genotype-phenotype correlations, clinical outcomes, and causes of death in patients with RBM20-associated cardiomyopathy and review the current literature. METHODS: The cohort included patients with cardiomyopathy harboring pathogenic (P) or likely pathogenic (LP) RBM20 variants. For survival and regression analysis, a control group matched for sex, age, and presence of left ventricular dysfunction was included. Additionally, a comprehensive literature search was conducted. RESULTS: Sixty-two patients (45 % male, 42 ± 15 years at presentation) were included. We found 11 truncating variants. Patients with truncating variants diagnosed with HF were older compared to patients with missense variants (mean age 62 ± 9 vs. 45 ± 14; p = 0.01). Over a median follow-up duration of 5.0 [1.0-10.5] years, 21 (34 %) patients reached the composite endpoint, with 19 (31 %) patients experiencing malignant ventricular arrhythmia (VA) (mean age 45 ± 15 years, 63 % males). Males exhibited higher risk for the composite endpoint (log-rank p = 0.02), particularly for VA (log-rank p = 0.007). The literature review analyzed 34 studies comprising 678 patients (53 % male). In these studies, 123 (24 %) patients experienced a VA, 58 (12 %) underwent a heart transplant or were treated with LVAD, and 52 (11 %) died. CONCLUSION: This multicenter study highlights the severe phenotype associated with LP/P RBM20 variants, with a high incidence of VA, particularly in males. Additionally, this study presents 11 truncating variants mainly observed in older individuals.