Abstract
BACKGROUND: Multiple genes have been associated with familial dilated cardiomyopathy (DCM). However, the role of genetic factors in sporadic DCM (SDCM) remains unclear. Therefore, we studied the genetic variations in Chinese patients with SDCM. METHODS: Sixty-six unrelated Chinese patients (mean age 49.1±17.0 years; 71% male) diagnosed with SDCM were enrolled. The clinical history and genomic DNA of the cohort were collected and examined. The exons of 24 genes closely associated with familial DCM (ABCC9, ACTC1, ACTN2, DES, LAMA4, LDB3, LMNA, MYBPC3, MYH6, MYH7, MYPN, PLN, PSEN1, PSEN2, RBM20, SCN5A, SGCD, TAZ, TCAP, TMPO, TNNI3, TNNT2, TPM1, and VCL) were sequenced using targeted next-generation sequencing method. All called nonsynonymous variants and their occurrence frequencies were compared against population data from public databases. And the nonsynonymous variants were also evaluated for pathogenicity by PolyPhen 2 (PP2) and Sorts Intolerant From Tolerant (SIFT) algorithms. RESULTS: Eighty-five nonsynonymous variants were detected in 17 genes. The variants and their occurrence frequencies in the patients were compared against population data from the 1000 Genomes and NHLBI (National Heart, Lung, and Blood Institute) Go Exome Sequencing Project. Forty-nine nonsynonymous variants had occurrence frequencies that were significantly higher in the study patients than in the general population, indicating that they have the potential to increase the risk of DCM. The risk variants were distributed in 40 (61%) patients, among whom 25 carried a single variant, while the remaining patients carried multiple (2 to 4) variants. Risk variants occurred more frequently in MYBPC3 (14% of the patients), SCN5A (14%), MYH7 (12%), MYPN (9%), and LDB3 (8%), as verified by Poisson distribution analysis, which were considered "the five risky genes". CONCLUSIONS: We found that genetic variants with potential risk for DCM were commonly present in SDCM patients, indicating that genetic factors contribute to the pathogenesis, and (probably) the onset, of DCM in these patients.