Malignant arrhythmias and advanced heart failure in patients with RBM20 cardiomyopathy: a single center cohort study and review of the literature
Authors: Tukker M A , Te Rijdt W P , Hajdarpasic A , Caliskan K 
Published: November 2023

Background

Sudden cardiac death (SCD), and death rate attributable to heart failure (HF) are common causes of death in the general population. Both are seen in cardiomyopathy patients. RBM20 mutations associated with a cardiomyopathy phenotype and a high risk of SCD and HF.

Purpose

The aim of this study is to investigate the genotype-phenotype correlations, and clinical outcomes of the RBM20 mutations.

Methods

Peripheral blood from patients was drawn as a routine diagnostic procedure and genomic DNA extracted according to standard protocols. Patients were tested for at least 45 cardiomyopathy-related genes included in the Dutch core panel. 23 patients with a likely pathogenic or pathogenic RBM20 mutation and a cardiomyopathy phenotype were retrospectively enrolled in a single-center cohort. Patient data on clinical characteristics, imaging and pathology were extracted retrospectively. Furthermore, a literature search was conducted for a literature review on RBM20 mutations in cardiomyopathies. Peer reviewed studies with patients aged 18 or older, a RBM20 mutation, and a cardiomyopathy were included.

Results

Whole genome sequencing found 5 different RBM20 protein altering mutations. The c.1900C&gt;T mutation was the most frequently seen in 18 patients. Four RBM20 mutations were novel mutations; c.1912, c.2919, c.414 and c.1118_1119 (Table1). The 23 patients had a mean age of 52 ± 15 years, and 13 (59%) were male. The phenotype was predominantly dilated cardiomyopathy (DCM). This was seen in 18 (82%)patients compared to 2 (12%) noncompaction cardiomyopathy (NCCM) patients. Nine (41%) patients had experienced malignant ventricular arrhythmia (VA). The mean age of first VA was 49 ± 10 years. An implantable cardioverter-defibrillator (ICD) was implanted in 13 (57%) patients, and gave appropriate therapy in 5 (23%) patients compared to 1 (9%) patient receiving inappropriate therapy. Ten (46%) patients were diagnosed with heart failure (HF) at a mean age of 50 ± 11 years. One patient died of heart failure, while 5 (25%) patients underwent heart transplantation (HTx). Delayed enhancement (DE) was shown on MRI in 5 (50%) patients, of which 3 had DE located in the mid-myocardial and inferolateral segments. They all had c.1900C&gt;T, but did not differ in clinical outcomes compared to patients without DE. The literature review included 32 studies with 394 total patients. Five studies reported on c.1900C&gt;T, of which 4 case reports/series and 1 cohort study. The mean age at diagnosis was lower in 4 studies and varied between 26 and 52 years compared to 51 ± 15 years in our c.1900C&gt;T group. The prevalence of VA was 66%-100% in the case reports/series, and 28% in the cohort study. In our cohort had 5 (42%) patients a VA.

Conclusion

This study found 4 novel RBM20 mutations. Moreover, the RBM20 mutation phenotype was predominantly DCM combined with a high prevalence of malignant VA and/or HF, which both had an peak age of early onset between 45-54 years.