Dilated cardiomyopathy (DCM) is a genetically heterogeneous disease with more than 100 so-called disease genes reported. Here, the frequencies of rare variants in the protein-coding regions of 56 commonly tested genes in 2538 patients with DCM were defined and compared with 912 healthy controls and a reference population of 60,706 to determine association with significant Clinically interpretable genes closely associated with sexual monogenic DCM. Rare variant burden of 56 putative DCM genes was assessed using the TruSight cardiac sequencing panel in 1040 patients with DCM and 912 healthy volunteers using the same sequencing and bioinformatics processing. Data from 1498 DCM patients sequenced in the Diagnostic Laboratory and Exome Aggregation Consortium database were further pooled for meta-analysis.
TTN and DSP cutoff variants were associated with DCM in all comparisons. MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1 and VCL variants were significantly enriched in selected patients, and the last 2 genes may be mainly responsible for the early onset of DCM. Overall, rare variants in these 12 genes explained 17% of cases in the outpatient cohort, which represented the broad range of adult DCM patients, and 26% of familial and early-onset DCM cases in the diagnostic referral cohort. While other genes lack significant clinical significance, a limited role in disease cannot be ruled out.
Robust disease associations with 12 genes were observed in the largest DCM cohort to date, highlighting their importance in DCM sex. Other genes will need to be rigorously evaluated in clinical work to determine their validity as Mendelian DCM genes, but currently have limited value in DCM diagnosis.
All sequenced genes are shown in the figure below,
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The clinically significant genes associated with DCM are shown in the table below,
DCM is rich in gene variants as shown in the figure below,
Circulation. 2020;141:387–398.