ClinicalGeneticGenetic variation in the alternative splicing regulator RBM20 is associated with dilated cardiomyopathy
Introduction
Idiopathic dilated cardiomyopathy (DCM) is a common disease with an estimated prevalence of 36.5 per 100,000 individuals1 and is associated with substantial mortality.2, 3, 4 The pathophysiologic mechanisms underlying DCM are heterogeneous, although there has been a long-standing appreciation of a heritable component to DCM.5, 6 Estimates suggest that up to one-third of individuals with DCM have familial disease.7, 8, 9, 10, 11 Indeed, numerous mutations that are believed to underlie familial DCM have been identified.12, 13, 14, 15, 16, 17, 18, 19, 20, 21 Among the most prevalent of these are mutations in lamin A/C and β-myosin heavy chain, each accounting for up to 10% of cases of familial DCM in some series.22, 23
In 2006, a susceptibility locus for DCM was mapped to chromosome 10q25 in 2 large families with DCM, fibrosis, and sudden cardiac death (SCD).24 Recently, Brauch et al25 identified a missense mutation in exon 9 of the ribonucleic acid (RNA)-binding motif protein 20 (RBM20) at the chromosome 10q25 locus that was responsible for the disease in one of the families. Screening of the RBM20 gene in an additional 278 probands with DCM of European descent identified 3 additional mutations. RBM20 is highly expressed in cardiac tissues and regulates splicing by processing premessenger RNA.25 RBM20 mutations in exon 9 were found in 3% of all the DCM cases tested and in over 13% of those with a history of SCD. Out of the 44 subjects with RBM20 mutations, 39 had clinically aggressive DCM and 9 had ventricular tachycardia.25
We therefore sought to (1) determine the prevalence of mutations in RBM20 in a large, multiracial cohort with DCM; (2) examine the clinical characteristics and outcomes of mutation carriers, including DCM-related outcomes such as atrial fibrillation (AF), ventricular arrhythmias, heart transplant, and mortality; and (3) determine whether common genetic variation in RBM20 alters clinical outcomes in patients with dilated or ischemic cardiomyopathy.
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Study subjects
All subjects included in this analysis were enrolled in the Genetic Risk Assessment of Defibrillator Events (GRADE) study.26 Subjects with DCM were recruited from the University of Pittsburgh Medical Center, Mid Ohio Cardiology, Emory University, Pittsburgh Veterans Affairs Medical Center, and Massachusetts General Hospital. Included subjects were aged at least 18 years and had significant left ventricular systolic dysfunction, defined as a left ventricular ejection fraction of 30% or less by
Results
The total GRADE study consists of 1465 individuals of which 283 individuals have DCM (Table 1). For individuals with DCM, the mean age was 58 ± 13 years, 182 (64%) were men, and 204 (72%) were of European ancestry. Among the subjects with DCM, 30 experienced ICD shocks, 23 received subsequent heart transplants, and 32 died over a mean follow-up time of 24.2 ± 17.1 months. Of the 1182 subjects with ischemic cardiomyopathy, the mean age was 65 ± 10 years, 1040 (88%) were men, and 1028 (87%) were
Discussion
In our large, multiethnic cohort of subjects with DCM, we identified mutations in coding regions of RBM20 in about 3% of individuals.
The spliceosome is a complex of specialized RNA and serine-arginine rich protein subunits that removes intron from a transcribed pre-mRNA segment. SR proteins have 2 major domains: RS domain (rich in arginine–serine repeats) and RNA-recognition motif that recognizes specific RNA sequences typically located within exons. RBM20 is a member of the SR protein family
Conclusions
We have identified mutations in RBM20 in approximately 3% of our sample of individuals with DCM. Mutations in RBM20 did not adversely affect survival or ventricular arrhythmias in subjects with DCM.
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M.M. Refaat, S.A. Lubitz, B. London, and P.T. Ellinor contributed equally to this manuscript.