The diagnosis of cardiomyopathy often relies on the subjective judgment of pathologists due to the variety of morphologic changes in the condition and its low specificity. This uncertainty can contribute to unexplained sudden cardiac deaths (USCD). To enhance the accuracy of hereditary cardiomyopathy diagnosis in forensic medicine, we proposed a combination of molecular autopsy and pathologic autopsy. By analyzing 16 deceased patients suspected of cardiomyopathy, using whole exome sequencing (WES) in molecular autopsy, and applying a combined diagnostic strategy, the study found pathogenic or likely pathogenic variants in 6 cases. Out of the 16 cases, cardiomyopathy was confirmed in 3, while 3 exhibited conditions consistent with it. Data for 4 cases was inconclusive, and cardiomyopathy was ruled out in 6. Notably, a novel variant of the TTN gene was identified. This research suggests that a grading diagnostic strategy, combining molecular and pathological evidence, can improve the accuracy of forensic cardiomyopathy diagnosis. This approach provides a practical model and strategy for precise forensic cause-of-death determination, addressing the limitations of relying solely on morphologic assessments in cardiomyopathy cases, and integrating genetic information for a more comprehensive diagnosis.

UNASSIGNED: To search for significant biomarkers associated with sudden death (SD).
UNASSIGNED: Differential genes were screened by comparing the whole blood samples from 15 cases of accidental death (AD) and 88 cases of SD. The protein-protein interaction (PPI) network selects core genes that interact most frequently. Machine learning is applied to find characteristic genes related to SD. The CIBERSORT method was used to explore the immune-microenvironment changes.
UNASSIGNED: A total of 10 core genes (MYL1, TNNC2, TNNT3, TCAP, TNNC1, TPM2, MYL2, TNNI1, ACTA1, CKM) were obtained and they were mainly related to myocarditis, hypertrophic myocarditis and dilated cardiomyopathy (DCM). Characteristic genes of MYL2 and TNNT3 associated with SD were established by machine learning. There was no significant change in the immune-microenvironment before and after SD.
UNASSIGNED: Detecting characteristic genes is helpful to identify patients at high risk of SD and speculate the cause of death.

To better understand the cause of sudden unexplained death, our group evaluated the scientific results of related studies in a global context. A systematic search of the Web of Science, PubMed and MEDLINE databases identified 2001 studies related to this field published from 1997 to 2020. The studies were analyzed using bibliometric methods, and statistical maps were drawn to explore research trends and research frontiers. Sudden cardiac death and sudden unexpected epilepsy death were the two major causes of sudden unexplained deaths. With the rapid development of high-throughput sequencing technology and bioinformatics in the past 10 years, molecular autopsy has become an effective research method as well as a research hotspot for exploring the cause of sudden unexplained deaths. However, molecular autopsy is underutilized in the investigation of sudden unexpected death in epilepsy. Developing standardized guidelines for diagnostic strategies for the deceased and their families, expanding the screening of mutation spectrum of related diseases, studying the association between variants and diseases in complex genetic diseases, and improving variants interpretation guidelines and disease sequencing databases are future research directions.

Aortic dissection (AD) usually remains undiagnosed, but its manifestation is abrupt and is associated with high morbidity and poor prognosis, leading to sudden cardiac death. Variants in COL family genes are associated with AD. In case 1, a 32-year-old Chinese man was admitted to the hospital with complaints of abdominal pain and died on the next day. In case 2, a 36-year-old Chinese woman was admitted to the hospital because of waist pain and died the next afternoon. According to autopsy findings, the cause of death in both cases was an acute cardiac tamponade, which was attributed to AD rupture. Whole-exome sequencing was performed on the blood collected from the hearts of the two deceased patients. Positive variants in COL family genes were found in both cases, without positive variants in other AD-associated genes. In case 1, a novel, likely pathogenic, missense variant was identified in COL6A1. In case 2, we identified one novel, likely pathogenic, frameshift deletion in COL23A1 and one novel, likely pathogenic, missense mutation in COL1A2. Based on these two cases, physicians should consider the role and significance of COL family gene mutations in AD in young patients. Furthermore, molecular anatomy is clearly necessary and significant in cases of sudden cardiac death attributed to AD, particularly in younger individuals.

Malignant hyperthermia (MH) is an autosomal dominant disorder characterized by abnormal calcium homeostasis in skeletal muscles in response to triggering agents. Autopsy, morphology, and genetic analysis were performed on a 19-year-old man who died rapidly after exposure to sevoflurane during maxillofacial surgery. Muscle spasm around the operation area and limb rigidity occurred and renal tubules full of myoglobin casts were observed by microscopy. Ultrastructural changes in the skeletal muscles and the myocardium were detected by transmission electron microscopy (TEM). Genetic analysis disclosed a ryanodine receptor type 1 (RYR1) gene mutation and a nucleoide mutation in chromosome 19q (G1021A) in the deceased and his father. According to the fore mentioned results, the relationship between the cause of death and MH was confirmed. Thus, genetic analysis can be an important procedure in diagnosing MH.