title: The genetics of dilated cardiomyopathy: a prioritized candidate gene study of LMNA, TNNT2, TCAP, and PLN.
abstract: BACKGROUND
  Dilated cardiomyopathy (DCM), which is characterized by left ventricular enlargement and systolic dysfunction, is divided into cases with a clear predisposing condition (eg, hypothyroidism, chemotherapeutic agents, alcoholism, ischemia) and those of unknown cause (idiopathic DCM). Many cases (20%-35%) of DCM are familial, implicating a genetic contribution to the etiology. More than 30 genes have been identified, many involving "private" mutations not shared among families. Evidence suggests that nonfamilial cases also have a genetic predisposition, again involving many genes. The goal of this study was to identify mutations in genes associated with DCM in a Québec study sample including familial and nonfamilial DCM cases.
  
  
  OBJECTIVE
  A prioritized gene study conducted within a framework for the classification of identified genetic variants could yield etiological information even in the absence of family data.
  
  
  METHODS
  We sequenced 4 previously identified genes: lamin A/C (LMNA), cardiac troponin T type 2 (TNNT2), titin-cap (TCAP), and phospholamban (PLN).
  
  
  RESULTS
  We discovered a nonsense mutation in the LMNA gene and a frameshift mutation in the TNNT2 gene, as well as other clinically significant variants that were not observed in publicly available databases or in Québec-based controls. PLN was sequenced to investigate a previously published promoter variant. However, our data confirm that this variant does not have a causal role in DCM.
  
  
  CONCLUSIONS
  Despite high locus and allele heterogeneity, we demonstrate that a prioritized gene study, combined with next-generation exome-sequencing data, can be fruitful for the identification of DCM mutations.
authors.affiliation: Department of Biology, McGill University, Montréal, Québec, Canada; The Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.
authors.forename: Marika
authors.initials: M
authors.lastname: Hirtle-Lewis
authors.forename: Katia
authors.initials: K
authors.lastname: Desbiens
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ruel
authors.forename: Nicholas
authors.initials: N
authors.lastname: Rudzicz
authors.forename: Jacques
authors.initials: J
authors.lastname: Genest
authors.forename: James C
authors.initials: JC
authors.lastname: Engert
authors.forename: Nadia
authors.initials: N
authors.lastname: Giannetti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D016022:Case-Control Studies; D018389:Codon, Nonsense; D064211:Connectin / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D016368:Frameshift Mutation; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011792:Quebec; D020107:Troponin T / Q000235:genetics*; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D018389:Codon, Nonsense; D064211:Connectin; D034904:Lamin Type A; D020107:Troponin T; D000099211:Phospholamban; C494847:LMNA protein, human; C577292:TCAP protein, human; C545568:TNNT2 protein, human
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