A novel ACTA2 variant in sudden fatal familial thoracic aortic dissection: literature review and genotype-phenotype expansion.

Thoracic aortic dissection (TAD) is a life-threatening emergency frequently linked to underlying genetic variants, particularly in familial cases. Molecular autopsy has become increasingly valuable in forensic practice for identifying occult heritable disorders when routine autopsy alone cannot fully clarify the cause of death. Here, we report a 17-year-old male who died suddenly due to pericardial tamponade caused by ruptured TAD. Gene testing identified a novel ACTA2 variant, c.155_162delinsGCACA. This indel leads to two amino acid substitutions (p.K52_D53delinsST) and a deletion (p.S54del), involving evolutionarily conserved residues. Histological examination showed aortic medial degeneration, characterized by elastic fiber rupture and disorganized arrangement of smooth muscle cells. Family screening confirmed the variant was inherited from his mother, with his elder sister also carrying it; both the mother and sister exhibited abnormal aortic calcification and congenital heart disease. Our systematic review revealed that pathogenic ACTA2 variants frequently involve multiple organ systems. This multisystem pattern enhances the forensic value of genetic testing by providing additional phenotypic clues that help determine the underlying cause of sudden death when routine autopsy findings are insufficient. By identifying this novel variant, our study expands the ACTA2 variants spectrum relevant to forensic molecular autopsy and reinforces the importance of incorporating postmortem genetic testing into death investigations, particularly in unexplained fatal aortic events.