title: Nonsense mutations in BAG3 are associated with early-onset dilated cardiomyopathy in French Canadians.
abstract: BACKGROUND
  Dilated cardiomyopathy (DCM) is a major cause of heart failure that may require heart transplantation. Approximately one third of DCM cases are familial. Next-generation DNA sequencing of large panels of candidate genes (ie, targeted sequencing) or of the whole exome can rapidly and economically identify pathogenic mutations in familial DCM.
  
  
  METHODS
  We recruited 64 individuals from 26 DCM families followed at the Montreal Heart Institute Cardiovascular Genetic Center and sequenced the whole exome of 44 patients and 2 controls. Both affected and unaffected family members underwent genotyping for segregation analysis.
  
  
  RESULTS
  We found 2 truncating mutations in BAG3 in 4 DCM families (15%) and confirmed segregation with disease status by linkage (log of the odds [LOD] score = 3.8). BAG3 nonsense mutations conferred a worse prognosis as evidenced by a younger age of clinical onset (37 vs 48 years for carriers and noncarriers respectively; P = 0.037). We also found truncating mutations in TTN in 5 families (19%). Finally, we identified potential pathogenic mutations for 9 DCM families in 6 candidate genes (DSP, LMNA, MYH7, MYPN, RBM20, and TNNT2). We still need to confirm several of these mutations by segregation analysis.
  
  
  CONCLUSIONS
  Screening an extended panel of 41 candidate genes allowed us to identify probable pathogenic mutations in 69% of families with DCM in our cohort of mostly French-Canadian patients. We confirmed the prevalence of TTN nonsense mutations in DCM. Furthermore, to our knowledge, we are the first to present an association between nonsense mutations in BAG3 and early-onset DCM.
authors.affiliation: Centre de Recherche, Montreal Heart Institute, Montréal, Québec, Canada; Départment de Médecine, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chami
authors.affiliation: Centre de Recherche, Montreal Heart Institute, Montréal, Québec, Canada; Départment de Médecine, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Rafik
authors.initials: R
authors.lastname: Tadros
authors.affiliation: Centre de Recherche, Montreal Heart Institute, Montréal, Québec, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Lemarbre
authors.affiliation: Centre de Recherche, Montreal Heart Institute, Montréal, Québec, Canada.
authors.forename: Ken Sin
authors.initials: KS
authors.lastname: Lo
authors.affiliation: Centre de Recherche, Montreal Heart Institute, Montréal, Québec, Canada.
authors.forename: Mélissa
authors.initials: M
authors.lastname: Beaudoin
authors.affiliation: Centre de Recherche, Montreal Heart Institute, Montréal, Québec, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Robb
authors.affiliation: Départment de Médecine, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada; Centre de Recherche, CHU Sainte-Justine, Montréal, Québec, Canada.
authors.forename: Damian
authors.initials: D
authors.lastname: Labuda
authors.affiliation: Centre de Recherche, Montreal Heart Institute, Montréal, Québec, Canada; Départment de Médecine, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.affiliation: Centre de Recherche, Montreal Heart Institute, Montréal, Québec, Canada; Départment de Médecine, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Normand
authors.initials: N
authors.lastname: Racine
authors.affiliation: Centre de Recherche, Montreal Heart Institute, Montréal, Québec, Canada; Départment de Médecine, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada. Electronic address: mario.talajic@umontreal.ca.
authors.forename: Mario
authors.initials: M
authors.lastname: Talajic
authors.affiliation: Centre de Recherche, Montreal Heart Institute, Montréal, Québec, Canada; Départment de Médecine, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada. Electronic address: guillaume.lettre@umontreal.ca.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lettre
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D017668:Age of Onset; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D002170:Canada / Q000453:epidemiology; D002311:Cardiomyopathy, Dilated / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D018389:Codon, Nonsense; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005602:France / Q000208:ethnology; D008040:Genetic Linkage; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; D018389:Codon, Nonsense; D004247:DNA