title: Genetic variation in the alternative splicing regulator RBM20 is associated with dilated cardiomyopathy.
abstract: BACKGROUND
  Dilated cardiomyopathy (DCM) is a leading cause of heart failure and death. The etiology of DCM is genetically heterogeneous.
  
  
  OBJECTIVE
  We sought to define the prevalence of mutations in the RNA splicing protein RBM20 in a large cohort with DCM and to determine whether genetic variation in RBM20 is associated with clinical outcomes.
  
  
  METHODS
  Subjects included in the Genetic Risk Assessment of Defibrillator Events (GRADE) study were aged at least 18 years, had an ejection fraction of ≤30%, and an implantable cardioverter-defibrillator (ICD). The coding region and splice junctions of RBM20 were screened in subjects with DCM; 2 common polymorphisms in RBM20, rs942077 and rs35141404, were genotyped in all GRADE subjects.
  
  
  RESULTS
  A total of 1465 subjects were enrolled in the GRADE study, and 283 with DCM were screened for RBM20 mutations. The mean age of subjects with DCM was 58 ± 13 years, 64% were males, and the mean follow-up time was 24.2 ± 17.1 months after ICD placement. RBM20 mutations were identified in 8 subjects with DCM (2.8%). Mutation carriers had a similar survival, transplantation rate, and frequency of ICD therapy compared with nonmutation carriers. Three of 8 subjects with RBM20 mutations (37.5%) had atrial fibrillation (AF), whereas 19 subjects without mutations (7.4%) had AF (P = .02). Among all GRADE subjects, rs35141404 was associated with AF (minor allele odds ratio = 0.62; 95% confidence interval = 0.44-0.86; P = .006). In the subset of GRADE subjects with DCM, rs35141404 was associated with AF (minor allele odds ratio = 0.58; P = .047).
  
  
  CONCLUSIONS
  Mutations in RBM20 were observed in approximately 3% of subjects with DCM. There were no differences in survival, transplantation rate, and frequency of ICD therapy in mutation carriers.
authors: Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA.
authors: Marwan M
authors: MM
authors: Refaat
authors: Steven A
authors: SA
authors: Lubitz
authors: Seiko
authors: S
authors: Makino
authors: Zahid
authors: Z
authors: Islam
authors: J Michael
authors: JM
authors: Frangiskakis
authors: Haider
authors: H
authors: Mehdi
authors: Rebecca
authors: R
authors: Gutmann
authors: Michael L
authors: ML
authors: Zhang
authors: Heather L
authors: HL
authors: Bloom
authors: Calum A
authors: CA
authors: MacRae
authors: Samuel C
authors: SC
authors: Dudley
authors: Alaa A
authors: AA
authors: Shalaby
authors: Raul
authors: R
authors: Weiss
authors: Dennis M
authors: DM
authors: McNamara
authors: Barry
authors: B
authors: London
authors: Patrick T
authors: PT
authors: Ellinor
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing / Q000235:genetics; D001145:Arrhythmias, Cardiac / Q000453:epidemiology / Q000209:etiology / Q000235:genetics / Q000628:therapy; D002304:Cardiac Pacing, Artificial / Q000379:methods*; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000628:therapy; D017147:Defibrillators, Implantable; D005260:Female; D016027:Heart Transplantation / Q000706:statistics & numerical data*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D022821:RNA Splice Sites / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics*; D018570:Risk Assessment; D013318:Stroke Volume; D015996:Survival Rate; D014481:United States / Q000453:epidemiology
chemical_list: D022821:RNA Splice Sites; D016601:RNA-Binding Proteins; C543725:ribonucleic acid binding motif protein 20, human