Introduction: We have not yet fully leveraged and integrated large-scale "omics" datasets with functional analyses to discover potential drivers of cardiomyopathy. My study addresses the knowledge gap. Methods: RNA sequence (RNA-Seq) variant detection, transcriptome profiling, and pathway analyses to model drug-refractory dilated cardiomyopathy (drDCM), discover drDCM/DCM microRNAs and novel variants using the BaseSpace sequencing hub and Ingenuity Pathway Analysis. Dataset Sources: NCBI Sequence Read Archive. Datasets: RNA-Seq(n = 6 DCM cases; n = 4 controls), exome sequence DCM families(n = 3 Italians; n = 5 Italians; n = 5 Chinese), Hap Map project(n = 5 Caucasians; n = 5 Asians), drDCM variant replication and DCM association analyses(n = 128 cases; n = 15 and 19 controls). Statistics: T-tests in calculating q-values for pairwise differential gene expression; chi-square tests to determine independence among variables, Fisher's Exact Tests and overlap p?value for the pathways, diseases, functions, and upstream regulators, p-scores to rank networks, z-scores to determine affected functions and likely transcriptional regulators. Results: ECHS1(enoyl-CoA hydratase, short chain 1: q = 0.013927), BAG1(BCL2 associated athanogene 1: q = 0.00975), and RHOD(ras homolog family member D: q = 0.012379) are associated with drDCM, and ITGAV(integrin subunit alpha V) with drDCM(q = 0.00205554) and DCM(q = 0.0368924). There is a relationship between mutations in ECHS1(V11A; rs10466126: p = 0.02496) and in BAG1(G45R; rs1071545: p = 1.94E-06) with drDCM, and in ITGAV(V783I; rs2230616) with drDCM(p = 0.0001591) and DCM(p = 2.455e-08). ECHS1 is associated with valine(--log(p) = 3.39), isoleucine(log(p) = 2.34) and fatty acid(--log(p) = 2.83) catabolism, BAG1 with glucocorticoid receptor signaling(--log(p) = 3.26) and protein ubiquitination(drDCM:--log(p) = 5.42), and ITGAV with the role of tissue factor in cancer(DCM:--log(p) = 2.975;drDCM:--log(p) = 5.02), NFB activation by viruses(DCM:--log(p) = 2.279;drDCM:--log(p) = 3.16), glioma invasiveness(DCM:--log(p) = 2.688;drDCM:--log(p) = 2.64), paxillin(DCM:--log(p) = 2.47;drDCM:--log(p) = 1.34), integrin(DCM:--log(p) = 2.125;drDCM:--log(p) = 1.55) and IL-8(DCM:--log(p) = 1.377;drDCM:--log(p) = 2.43) signaling. Data revealed five drDCM and eleven DCM associated novel variants, and twenty drDCM and twelve DCM related microRNAs. ECHS1(log 2(foldchange) = 1.63329) hosts a mirtron, MIR3944 expressed in drDCM (FPKM = 5.2857) and not in controls (FPKM = 0). Has-miR3944-3p is a putative target of BAG1(log2(foldchange) = 1.31978), and has-miR3944-5p of ITGAV(log2(foldchange) = 1.46107) and RHOD(log2(foldchange) = 1.28851).

Conclusion: I postulate that drDCM patients appear unresponsive to drugs because, in addition to cytoskeletal insults, they have nuclei and mitochondrial genomic errors that are intertwined with environmental stimuli, branched-chain amino-acids, and long-chain fatty-acids. I introduce an integrative data strategy that considers the interplay between the DNA, mRNA, and associated pathways, which represents a possible diagnostic, prognostic, biomarker, and treatment discovery approach in genetically heterogeneous diseases.