Genetic and epigenetic landscape of non-familial sudden cardiac death

Sudden cardiac death (SCD) remains a major global health challenge, characterized by high incidence, low survival rates, and often presenting as the first manifestation of underlying disease. This review provides a comprehensive overview of the genetic and epigenetic landscape of non-familial SCD, emphasizing the multifactorial nature of this complex clinical endpoint. We summarize common single nucleotide polymorphisms and insertion/deletion variants associated with SCD, identified through candidate-gene-based studies and genome-wide association studies, highlighting risk variants clustered in genes involved in cardiovascular function, signal transduction, and cellular metabolism. We also describe the main epigenetic mechanisms – including microRNAs, DNA methylation, and histone modifications – that may contribute to SCD susceptibility and pathogenesis. Tissue-based and circulating microRNAs can act as mechanistic regulators of SCD pathogenesis and have emerged as exploratory biomarker candidates. However, inconsistent directions of association, methodological heterogeneity, and limited independent validation currently preclude their clinical application. DNA methylation studies, though scarce, suggest potential roles for imprinted genes and oxidative stress pathways. Histone modifications and chromatin remodeling represent underexplored but promising areas. We conclude that addressing the missing heritability of SCD and translating these molecular insights into clinical practice will require large-scale, integrative, and multi-ethnic studies combining genomic, epigenomic, and clinical data with functional validation.