Case report: investigation of sudden unexpected death in the young using a molecular autopsy

Toefy, Tasneem

Case report: investigation of sudden unexpected death in the young using a molecular autopsy

Thesis / Dissertation

2026

Publisher

University of Cape Town

Department

Division of Forensic Medicine and Toxicology

Faculty

Faculty of Health Sciences

Abstract

Sudden unexpected death in the young (SUDY) refers to the abrupt death of individuals aged 1–50 years, often linked to cardiovascular, respiratory, metabolic, or infectious diseases. However, in some cases, no clear cause of death is identified during standard post-mortem examinations. Through a molecular autopsy, using massively parallel sequencing, this study aimed to identify genetic variants that may have contributed to the sudden demise of a 43-year-old female during a half-marathon in 2018. At the time, no cause of death was established, and DNA was retained at autopsy. Clinical exome sequencing was done using the Illumina TruSight One Panel and 11 773 genetic variants were identified. Using standard criteria, variants were filtered using BaseSpace Variant Interpreter and ten were prioritised for further evaluation. Pathogenicity was assessed, indicating one was benign, four were likely benign, four were variants of uncertain significance (VUS) and one was likely pathogenic (LP). Sanger sequencing confirmed the heterozygous VUS, which were all in cardiovascular-related genes, as well as the homozygous LP variant (CPS1 c.1030_1032delinsGCT (p.Thr344Ala)) linked to metabolic dysfunction. Consultation with a forensic pathologist revealed that three VUS (MYBPC3 (c.3224C>G (p.Thr1075Ser)), TMEM43 (c.982C>T (p.Arg328Trp)), and ANK2 (c.385-6C>T (splice site)) complimented pathology findings and may have explained death. However, histological cardiac tissue analysis and further clinical history are required to confirm these findings. Furthermore, the LP CPS1 variant may be poorly understood in terms of pathological relevance and overlooked as contributory to death. This study demonstrates the value of clinical exome sequencing in identifying genetic variants that may contribute to SUDY. The findings highlight the complexity of linking genetic variations to sudden death and underscore the need for further research into metabolic and cardiovascular genetic mutations. Integrating genetic, pathological, and clinical data is essential to improve the understanding, prevention, and forensic investigation of SUDY.

Keywords

sudden unexpected death in the young (SUDY)

post-mortem

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