Aims Despite considerable progress being made in genetic diagnostics for dilated cardiomyopathy (DCM) using panels of the most prevalent genes, the cause remains unsolved in a substantial percentage of patients. We hypothesize that several previously described DCM genes with low or unknown prevalence have been neglected, which, if catalogued, could increase the yield of diagnostic DCM testing. The aim of this study is to catalogue all genetic evidence on DCM comprehensively. Methods and results We have conducted a systematic literature search on PubMed, Embase, and OMIM to find genes implicated in syndromic and non‐syndromic DCM and peripartum cardiomyopathy (PPCM). Our search yielded 110 nuclear protein‐coding genes and 24 mitochondrial DNA genes. For nuclear genes, in addition to 42 genes sufficiently reviewed previously (group A), we provide a comprehensive annotation of the level of genetic evidence for the remaining 68 genes (group B). Next, we investigated the tissue specificity of the collected genes using public RNA sequencing data. We show that genes primarily expressed in heart and skeletal muscle are more likely to result in DCM with possible skeletal myopathies, while genes expressed ubiquitously cause DCM with extramuscular manifestations. Conclusion This comprehensive analysis of DCM‐associated genes revealed a much higher number of genes than currently screened in diagnostics. Since most genes in group B have only been found mutated in single DCM patients or families, their importance for DCM genetic diagnostics needs to be validated in large cohorts. Targeted sequencing of validated DCM‐implicated protein‐coding genes and mitochondrial DNA, together with consideration of the tissue specificity of mutated genes, may facilitate further genotype–phenotype studies in DCM.

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Genetics plays an important role in the pathophysiology of cardiovascular diseases, and is increasingly being integrated into clinical practice. Since 2008, both capacity and cost-efficiency of mutation screening of DNA have been increased magnificently due to the technological advancement obtained by next-generation sequencing. Hence, the discovery rate of genetic defects in cardiovascular genetics has grown rapidly and the financial threshold for gene diagnostics has been lowered, making large-scale DNA sequencing broadly accessible. In this review, the genetic variants, mutations and inheritance models are briefly introduced, after which an overview is provided of current clinical and technological applications in gene diagnostics and research for cardiovascular disease and in particular, dilated cardiomyopathy. Finally, a reflection on the future perspectives in cardiogenetics is given.

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