Dilated Cardiomyopathy: A Genetic Journey from Past to Future

Dilated cardiomyopathy (DCM) is characterized by reduced systolic function and cardiac dilation. Cases without an identified secondary cause are classified as idiopathic dilated cardiomyopathy (IDC). Over the last 35 years, many cases of IDC have increasingly been recognized to be genetic in etiology with a core set of definitively causal genes in up to 40% of cases. While over 200 genes have been associated with DCM, the evidence supporting pathogenicity for most remains limited. Further, rapid advances in sequencing and bioinformatics have recently revealed a complex genetic spectrum ranging from monogenic to polygenic in DCM. These advances have also led to the discovery of causal and modifier genetic variants in secondary forms of DCM (e.g., alcohol-induced cardiomyopathy). Current guidelines recommend genetic counseling and screening, as well as endorsing a handful of genotype-specific therapies (e.g., device placement in LMNA cardiomyopathy). The future of genetics in DCM will likely involve polygenic risk scores, direct-to-consumer testing, and pharmacogenetics, requiring providers to have a thorough understanding of this rapidly developing field. Herein we outline three decades of genetics in DCM, summarize recent advances, and project possible future avenues for the field.