The Genetics of Dilated Cardiomyopathy: A Prioritized Candidate Gene Study of LMNA , TNNT2 , TCAP , and PLN

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. Hypothesis 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.