Sudden Unexpected Death after a mild trauma: The complex forensic interpretation of cardiac and genetic findings

A 55-year-old man affected by a psychotic disorder suddenly died during a quarrel with his father. The autopsy excluded traumatic causes of death, and the cardiac examination identified a severe cardiomegaly with biventricular dilatation of very likely multifactorial origin. Toxicological and pharmacogenetic analyses excluded a fatal intoxication and identified the presence of the antipsychotic drug fluphenazine in the therapeutic range in a normal metabolizer. The screening for genetic variations highlighted a novel heterozygous single-nucleotide variant in the exon 36: c 0.4750C>A (p.Pro1584Thr) of the Ryanodine Receptor Type 2 (RYR2) gene. The mutation detected can be classified as Likely Pathogenic according to the American College of Medical Genetics and Genomics (ACMG) criteria. RYR2 variation has been associated to catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease currently recognized as one of the most malignant cardiac channelopathies, expressed mostly in young patients, normally in the absence of structural heart disease. The victim late middle age, compared to juvenile onset of CPVT reported in literature, his clinical history, his structurally altered heart, circumstances at death and the absence of phenotype-related variations of dilated cardiomyopathy genes, suggested that the fatal arrhythmia could have been caused by an acquired form of dilated cardiopathy/cardiomyopathy. However, the contribution of the genetic variant to death cannot be completely ruled out, since the significance of a VUS or of a novel variant depends on the data available at the time of investigation, and should be periodically evaluated. We discuss the contribution of the structural alteration and of the variant detected, as well as the role of the molecular autopsy in forensic examination, which can make a significant contribution for inferring both cause and manner of death.