Interpretation of molecular autopsy findings in 45 sudden unexplained death cases: from coding region to untranslated region

Abstract

Sudden unexplained death (SUD) can affect apparently healthy adolescents and young adults with no prior clinical symptoms and no clear diagnostic findings at autopsy. Although primary cardiac arrhythmias have been shown to be the direct cause of death in the majority of SUD cases, the genetic predisposition contributing to SUD remains incompletely understood. Currently, molecular autopsy is considered to be an effective diagnostic tool in the multidisciplinary management of SUD, but the analysis focuses mainly on the coding region and the significance of many identified variants remains unclear. Recent studies have demonstrated the strong association between human disease and genetic variants in untranslated regions (UTRs), highlighting the potential role of UTR variants in the genetic predisposition to SUD. In this study, we searched for UTR variants with likely functional effects in the exome data of 45 SUD cases. Among 244 genes associated with cardiac diseases, three candidate variants with high confidence of pathogenicity were identified in the UTRs of SCO2, CALM2 and TBX3 based on a rigorous filtering strategy. A functional assay further validated the effect of these candidate variants on gene transcriptional activity. In addition, the constraint metrics, intolerance indexes, and dosage sensitivity scores of genes affected by the candidate variants were considered when estimating the consequence of aberrant gene expression. In conclusion, our study presents a practical strategy for UTR variant prioritization and functional annotation, which could improve the interpretation of molecular autopsy findings in SUD cohorts.