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Nonsense mutations in BAG3 are associated with early-onset dilated cardiomyopathy in French Canadians.
Chami, Nathalie; Tadros, Rafik; Lemarbre, François; Lo, Ken Sin; Beaudoin, Mélissa; Robb, Laura; Labuda, Damian; Tardif, Jean-Claude; Racine, Normand; Talajic, Mario; Lettre, Guillaume.
Afiliação
  • Chami N; Centre de Recherche, Montreal Heart Institute, Montréal, Québec, Canada; Départment de Médecine, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada.
  • Tadros R; Centre de Recherche, Montreal Heart Institute, Montréal, Québec, Canada; Départment de Médecine, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada.
  • Lemarbre F; Centre de Recherche, Montreal Heart Institute, Montréal, Québec, Canada.
  • Lo KS; Centre de Recherche, Montreal Heart Institute, Montréal, Québec, Canada.
  • Beaudoin M; Centre de Recherche, Montreal Heart Institute, Montréal, Québec, Canada.
  • Robb L; Centre de Recherche, Montreal Heart Institute, Montréal, Québec, Canada.
  • Labuda D; Départment de Médecine, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada; Centre de Recherche, CHU Sainte-Justine, Montréal, Québec, Canada.
  • Tardif JC; Centre de Recherche, Montreal Heart Institute, Montréal, Québec, Canada; Départment de Médecine, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada.
  • Racine N; Centre de Recherche, Montreal Heart Institute, Montréal, Québec, Canada; Départment de Médecine, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada.
  • Talajic M; 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.
  • Lettre G; 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.
Can J Cardiol ; 30(12): 1655-61, 2014 Dec.
Article em En | MEDLINE | ID: mdl-25448463
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: DNA / Cardiomiopatia Dilatada / Códon sem Sentido / Proteínas Adaptadoras de Transdução de Sinal / Proteínas Reguladoras de Apoptose Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Adult / Female / Humans / Male / Middle aged País/Região como assunto: America do norte / Europa Idioma: En Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: DNA / Cardiomiopatia Dilatada / Códon sem Sentido / Proteínas Adaptadoras de Transdução de Sinal / Proteínas Reguladoras de Apoptose Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Adult / Female / Humans / Male / Middle aged País/Região como assunto: America do norte / Europa Idioma: En Ano de publicação: 2014 Tipo de documento: Article