Beyond Conventional Autopsy: Recent Advances in Molecular Autopsy for Sudden Cardiac Death Investigation

Sudden cardiac death (SCD) is a leading cause of unexpected mortality worldwide and represents a major challenge in pathology, especially when conventional autopsy fails to identify a definitive cause of death. In these cases, molecular autopsy (MA) has emerged as a valuable diagnostic approach, enabling the identification of pathogenic genetic variants associated with inherited cardiomyopathies, channelopathies, and other cardiovascular diseases. This review provides a comprehensive overview of the current role of MA in the investigation of SCD, highlighting recent advances in postmortem genetic testing and their impact on forensic practice. The evolution of sequencing technologies, from targeted gene panels to whole-exome and whole-genome sequencing, as well as new long-read sequencing approaches, is discussed. Emphasis is placed on the interpretation of genetic variants according to current international guidelines, the integration of molecular findings with autopsy, histopathological, and toxicological investigations, and the importance of multidisciplinary collaboration between forensic pathologists, molecular geneticists, cardiologists, and genetic counselors. We also examine current challenges, including variants of uncertain significance, limited genotype–phenotype correlation, ethical considerations, and the need for standardized international protocols. Finally, we explore prospects, including multi-omics technologies, artificial intelligence-assisted variant interpretation, and improved data sharing initiatives, which may improve diagnostic accuracy and facilitate clinical translation. In addition to determining cause of death, MA has become an essential tool for identifying at-risk relatives through cascade screening, thus extending the role of forensic genetics from postmortem diagnosis to preventive cardiovascular medicine.