Exploring transcriptomic signatures in sudden unexplained death (SUD) cases.

Background: Molecular autopsy in sudden unexplained death (SUD) has successfully identified pathogenic variants in cardiovascular genes in a substantial proportion of cases, contributing to prevention strategies in family members. However, many SUD cases remain genetically unresolved, prompting investigations into other omics technologies to better understand the pathogenic mechanisms leading to a sudden death event. In this study, whole transcriptome sequencing was performed on heart samples from 43 SUD cases and 17 heart-healthy controls, with the aim to identify disease-specific transcriptome signatures in sudden unexplained death.

Results: PCA based on the top 500 genes with the highest variance among the samples showed no clear separation between SUD and controls or among the three SUD subgroups. DESeq2 identified 1,676 differentially expressed genes between SUD and controls with significantly upregulated genes involved in biological processes such as angiogenesis, blood vessel development, vasculogenesis and cell adhesion. Pathway analysis of the differentially expressed genes showed that most were downregulated and involved in amide/peptide biosynthesis and fatty acid metabolism. Additional analysis of SUD subgroups revealed unique gene expression patterns and highlighted differentially expressed genes within each subgroup.

Conclusion: Gene expression analysis of SUD heart tissue is a promising approach to identify cardiac disease-related pathways to further understand the pathological mechanisms leading to a sudden death event. However, due to the heterogeneity of the SUD cases and the unclear phenotype, further studies in larger cohorts are needed.