Rationale:
Dilated cardiomyopathy (DCM) is a leading cause of heart failure and have a genetic basis in 20-30% of cases. Genetic studies in familial DCM have found mutations identified in more than 30 genes. However, the genetics of sporadic DCM is still unknown.
Objective:
To provide new insights into the pathophysiology of sporadic DCM, a mutational screening on 30 DCM-causing genes in a cohort was performed.
Methods and Results:
Patients diagnosed with idiopathic DCM were recruited into the study and underwent clinical evaluation. Genomic DNA was isolated from the peripheral blood and then 30 genes (
ACTC, DES, SGCD, MYH7, TNNT2, TPM1, TTN, VCL, MYBPC3, CSRP3, ACTN2, PLN, LDB3, MYH6, ABCC9, TNNC1, TCAP, TNNI3, EYA4, TMPO, PSEN1/2, CRYAB, PDLIM3, MYPN, LAMA4, ILK, ANKRD1, RBM20, LMNA
, and
SCN5A
) of every sample were detected by next-generation sequencing. All called variants were compared against National Center for Biotechnology Information SNP Database build 137 and the March 2012 release of the 1000 Genomes project. All variants identified in the cohort were compared in ethnic-matched controls consisting of 197 adult Chinese from the 1000 Genomes. The pathogenicity of the variants absent from controls were evaluated by SIFT software. Sixty-six adult Chinese unrelated DCM patients were tested for up to 30 genes causing familial DCM. The mean age was 49.14±15.97 years. Every patient was detected nonsynonymous variants, and the total 87 variants were composed of 39 novel and 48 known. Among the whole 87 variants, 34 satisfied the criteria (1) absent from ethnic-matched controls and (2) altering evolutionary conservation of amino acid verified by SIFT analysis, which were considered pathogenic mutations, identified in 30 patients accounting for 45.45% of the cohort. The 2 most frequent genes involved in mutation positive patients were
SCN5A
(12.12%) and
MYH7
(10.61%).
Conclusions:
Mutant genes found in familial DCM were also common in sporadic DCM, and the discovery of novel mutations spanned the spectrum of DCM genetics, implicating that genetic etiologies play an important role in pathogenesis of sporadic DCM.
