Postmortem genetic testing in sudden unexplained death: A public health laboratory experience

Abstract

Sudden unexplained death in the young poses a diagnostically challenging situation for practicing autopsy pathologists, especially in the absence of anatomic and toxicological findings. Postmortem genetic testing may identify pathogenic variants in the deceased of such cases, including those associated with arrhythmogenic channelopathies and cardiomyopathies. The Wisconsin State Laboratory of Hygiene (WSLH) is a state-run public health laboratory which performs postmortem genetic testing at no cost to Wisconsin medical examiners and coroners. The current study examines sequencing data from 18 deceased patients (ages 2 months to 49 years, 5 females) submitted to WSLH, from 2016 to 2021. Panel-based analysis was performed on 10 cases, and whole exome sequencing was performed on the most recent 8 cases. Genetic variants were identified in 14 of 18 decedents (77.8%), including 7 with pathogenic or likely pathogenic variants (38.9%). Whole exome sequencing was more likely to yield a positive result, more variants per decedent, and a larger number of variants of uncertain significance. While panel-based testing may offer definitive pathogenic variants in some cases, less frequent variants may be excluded. Whole exome testing may identify rare variants missed by panels, but increased yield of variants of uncertain significance may be difficult to interpret. Postmortem genetic testing in young decedents of sudden unexplained death can provide invaluable information to autopsy pathologists to establish accurate cause and manner of death and to decedent's relatives to allow appropriate management. A public health laboratory model may be a financially advisable alternative to commercial laboratories for medical examiner's/coroner's offices.

Keywords: autopsy; cardiomyopathy; channelopathy; forensic pathology; next-generation sequencing; postmortem genetic testing; public health laboratory; sudden cardiac death; sudden unexpected death in the young; whole exome sequencing.