Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy

Abstract

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 incompletely defined. Methods and Results: To define the genetic architecture of RBM20 cardiomyopathy, we first established a database of RBM20 variants associated with cardiomyopathy and compared these to variants observed in the general population with respect to their location in the RBM20 coding transcript. We identified two regions significantly enriched for cardiomyopathy-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 titin (TTNtv) cardiomyopathy, and not significantly different from a cohort of patients with Lamin A/C associated (LMNA) cardiomyopathy. Conclusions: Our data establish RBM20 cardiomyopathy as a highly penetrant and arrhythmogenic cardiomyopathy. These findings underline the importance of arrhythmia surveillance and family screening in this disease and represent the first step in defining the genetic architecture of RBM20 disease causality on a population level. −/− mice demonstrate pro-arrhythmic calcium release from the sarcoplasmic reticulum 45. Parikh et al.

Sudden Cardiac Death in Hereditary Dilated Cardiomyopathy

“…Also associated with a higher risk of arrhythmic events are mutations in the FLNC gene, which encodes filamin proteins; the RNA-binding motif protein 20 gene (RBM20 gene), which encodes a protein that regulates splicing and the phospholamban (PLN) gene, which encodes a protein that inhibits a sarcoplasmic ATPase [21,27]. In a 2019 study, it was demonstrated that RBM20 mutation carriers were more likely to have NSVT and sustained VT than idiopathic DCM cohorts [28]. The AR-DCM phenotype is associated with a high risk of fatal arrhythmias.…”

Structural basis of UCUU RNA motif recognition by splicing factor RBM20

“…RBM20 was itself first identified in a search for a familial genetic basis of DCM in human patients (Brauch et al, 2009). Subsequent investigation has identified additional patients and mutations involving RBM20 related to DCM (Zhao et al, 2015b;Long et al, 2017;Wells et al, 2013;Waldmüller et al, 2015;Chami et al, 2014;Refaat et al, 2012;Rampersaud et al, 2011;Millat et al, 2011;Li et al, 2010;Robyns et al, 2019), as well as cardiac arrhythmia (Nielsen et al, 2018;Parikh et al, 2019), pediatric restrictive cardiomyopathy (Rindler et al, 2017) and left-ventricular non-compaction . Although representing only 3 % of idiopathic cases, patients with DCM that have mutant RBM20 correlate with earlier disease onset, high penetrance, and requirement for heart transplantation (Brauch et al, 2009;Li et al, 2010;Kayvanpour et al, 2017;Wells et al, 2013;Hey et al, 2019).…”

RBM20 mutations in left ventricular non‐compaction cardiomyopathy

“…RBM20 is composed of two zink finger domains, one RNA‐recognition motif (RRM)‐type RNA binding domain and an arginine‐/serine‐(RS)‐rich region. In 2019, two mutational hot spot regions in exons 9 and 11 of RBM20 have been recognized 26 . The majority of pathogenic RBM20 mutations is localized in the RS domain 11,18,19,23 .…”

“…In 2019, two mutational hot spot regions in exons 9 and 11 of RBM20 have been recognized. 26 The majority of pathogenic RBM20 mutations is localized in the RS domain. 11,18,19,23 Nevertheless, a global understanding of variant pathogenicity across the RBM20-coding transcript remains elusive.…”

“…An RBM20 patient registry has been assembled and reveals a high prevalence of sudden cardiac deaths and early onset cardiomyopathies. 26 In this clinical context, Sun et al 27 describe in the current issue of Pediatric Investigation two independent young LVNC patients carrying RBM20 missense mutations. Both mutations have been identified before in DCM patients.…”