Genetic determinants serve as the core driver of dilated cardiomyopathy, with 30%-50% of cases having a familial origin linked to mutations in sarcomeric, nuclear membrane, and ion channel genes.
This review summarizes the pathogenic genes of dilated cardiomyopathy and emphasizes the need to shift from single-gene therapies to broad-spectrum treatments targeting common pathological environments.
Dilated cardiomyopathy (DCM) is a primary myocardial disorder characterized by progressive ventricular dilatation and impaired myocardial systolic contractility, and it represents the most common form of cardiomyopathy globally. DCM drives a substantial worldwide disease burden, thus presenting a formidable and persistent challenge to global public health systems. The pathogenesis of DCM is marked by extreme etiological heterogeneity: 30%-50% of cases have a familial origin, with genetic determinants serving as the core driver of disease onset and progression. With the rapid advancement and widespread application of next-generation sequencing (NGS) technologies, a growing repertoire of DCM-causative genes has been successfully identified. These genes encode key functional proteins that regulate multiple core physiological processes in cardiomyocytes, including sarcomeric structure maintenance, intracellular signal transduction, and myocardial energy homeostasis. DCM-causing genes can be classified into multiple categories according to their functions. Sarcomeric protein genes (such as TTN, MYH7, and TNNT2) disrupt sarcomere assembly and contractile function through mechanisms such as haploinsufficiency and the toxic peptide hypothesis; mutations in nuclear membrane protein genes (such as LMNA and EMD) cause abnormal nuclear structure and disordered mechanotransduction signals; ion channel genes (such as SCN5A, CACNA1C, and RYR2) affect electrophysiological balance and calcium handling; desmosome-related genes (such as DSC2 and DSP) are associated with abnormal cell junctions and dysregulation of the Wnt/β-catenin pathway; KLF13, ETS1, and BMP10 are possible candidate genes for DCM with limited research; loss of function of RBM20 leads to abnormal splicing of TTN, CamkIIδ, RyR2, etc. and causes nuclear import defects as well as cytoplasmic RBM20-RNP granule toxicity, thereby driving ventricular dilation. These genes drive myocardial remodeling through common signaling pathways (such as ERK and TGF-β). Potential treatment strategies include gene-level interventions, targeted pathway inhibitors, and myosin activators. However, genetic heterogeneity results in a narrow applicable population for single-gene therapies. Future research needs to shift from targeting individual genes to improving the common pathological environment to achieve broad-spectrum treatment. Exploring upstream prevention of mutations or activation of endogenous repair mechanisms provides new directions for the treatment of DCM.
Zhang et al. (Sat,) conducted a review in Dilated cardiomyopathy. Genetic determinants serve as the core driver of dilated cardiomyopathy, with 30%-50% of cases having a familial origin linked to mutations in sarcomeric, nuclear membrane, and ion channel genes.