Genetic sequencing of prioritized candidate genes identified a nonsense mutation in LMNA and a frameshift mutation in TNNT2 in patients with dilated cardiomyopathy.
Observational
Can a prioritized candidate gene study identify causal mutations in familial and nonfamilial dilated cardiomyopathy?
A prioritized candidate gene study successfully identified clinically significant mutations in LMNA and TNNT2 in a Québec cohort of dilated cardiomyopathy patients.
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.
Hirtle‐Lewis et al. (Tue,) conducted a observational in Dilated cardiomyopathy. Genetic sequencing of LMNA, TNNT2, TCAP, and PLN vs. Québec-based controls and publicly available databases was evaluated on Identification of mutations associated with dilated cardiomyopathy. Genetic sequencing of prioritized candidate genes identified a nonsense mutation in LMNA and a frameshift mutation in TNNT2 in patients with dilated cardiomyopathy.