Abstract 15240: Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy.

Background: Variants in the cardiomyocyte-specific RNA splicing factor RBM20 have been linked to familial cardiomyopathy, but the causative genetic architecture and clinical consequences of this disease are poorly defined. Methods and Results: To define the genetic architecture of RBM20 variant disease causality, we first established a database of unique RBM20 variants associated with cardiomyopathy and compared these to unique variants observed in the general population with respect to their location in the RBM20 coding transcript (Figure 1). We identified two regions significantly enriched for cardiomyopathy (CM)-associated variants in exons 9 and 11. We then assembled a registry of 74 patients with RBM20 variants from 8 institutions across the world (44 index cases and 30 from cascade testing). This RBM20 patient registry revealed highly prevalent family history of sudden cardiac death (51%) and cardiomyopathy (72%) among index cases, and a high prevalence of composite arrhythmias (including AF, NSVT, ICD discharge and sudden cardiac arrest, 43%). Patients harboring variants in cardiomyopathy-enriched regions identified by our variant database analysis were enriched for these findings. Further, these characteristics were more prevalent in the RBM20 registry than in large cohorts of patients with DCM and TTNtv cardiomyopathy. Conclusions: This establishes RBM20 cardiomyopathy not only as a cause of inherited cardiomyopathy, but also as cause of a particularly highly penetrant and arrhythmogenic cardiomyopathy. These findings underline the importance of arrhythmia surveillance and family screening in these patients, and represent the first step in defining the genetic architecture of RBM20 disease causality on a population level. [ABSTRACT FROM AUTHOR]