title: Familial Dilated Cardiomyopathy Caused by a Novel Frameshift in the BAG3 Gene.
abstract: BACKGROUND
  Dilated cardiomyopathy, a major cause of chronic heart failure and cardiac transplantation, is characterized by left ventricular or biventricular heart dilatation. In nearly 50% of cases the pathology is inherited, and more than 60 genes have been reported as disease-causing. However, in 30% of familial cases the mutation remains unidentified even after comprehensive genetic analysis. This study clinically and genetically assessed a large Spanish family affected by dilated cardiomyopathy to search for novel variations.
  
  
  RESULTS
  Our study included a total of 100 family members. Clinical assessment was performed in alive, and genetic analysis was also performed in alive and 1 deceased relative. Genetic screening included resequencing of 55 genes associated with sudden cardiac death, and Sanger sequencing of main disease-associated genes. Genetic analysis identified a frame-shift variation in BAG3 (p.H243Tfr*64) in 32 patients. Genotype-phenotype correlation identified substantial heterogeneity in disease expression. Of 32 genetic carriers (one deceased), 21 relatives were clinically affected, and 10 were asymptomatic. Seventeen of the symptomatic genetic carriers exhibited proto-diastolic septal knock by echocardiographic assessment.
  
  
  CONCLUSIONS
  We report p.H243Tfr*64_BAG3 as a novel pathogenic variation responsible for familial dilated cardiomyopathy. This variation correlates with a more severe phenotype of the disease, mainly in younger individuals. Genetic analysis in families, even asymptomatic individuals, enables early identification of individuals at risk and allows implementation of preventive measures.
authors.affiliation: Medicine Department, School of Medicine, Cadiz, Spain.
authors.forename: Rocio
authors.initials: R
authors.lastname: Toro
authors.affiliation: Cardiovascular Genetics Center, IDIBGI, University of Girona, Girona, Spain.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Pérez-Serra
authors.affiliation: Cardiovascular Genetics Center, IDIBGI, University of Girona, Girona, Spain.|Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain.
authors.forename: Oscar
authors.identifier: http://orcid.org/0000-0001-5298-5276
authors.initials: O
authors.lastname: Campuzano
authors.affiliation: Cardiovascular Genetics Center, IDIBGI, University of Girona, Girona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Moncayo-Arlandi
authors.affiliation: Cardiovascular Genetics Center, IDIBGI, University of Girona, Girona, Spain.
authors.forename: Catarina
authors.initials: C
authors.lastname: Allegue
authors.affiliation: Cardiovascular Genetics Center, IDIBGI, University of Girona, Girona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Iglesias
authors.affiliation: Medicine Department, School of Medicine, Cadiz, Spain.
authors.forename: Alipio
authors.initials: A
authors.lastname: Mangas
authors.affiliation: Cardiovascular Genetics Center, IDIBGI, University of Girona, Girona, Spain.|Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain.|Cardiac Genetics Unit, Hospital Josep Trueta, University of Girona, Girona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Brugada
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000209:etiology* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004452:Echocardiography; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human