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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.', '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.', '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.
Are nonsense mutations in BAG3 associated with early-onset dilated cardiomyopathy in French Canadians?