Description of original award (Fiscal Year 2018, $450,243)
Sudden Unexpected Natural Death (SUND) in the Young (less than or equal to 50 years old) is a considerable forensic burden for medical examiners. Postmortem genetic testing is a powerful, cost-effective tool for cause of death determination in SUND, and life-saving for at-risk families. However, the current scope is limited to primarily testing cardiac related genes, leaving more than 50% cases negative. Two further studies are expected to improve diagnostic success. One is to test additional SUND associated genes, including those causing Sudden Unexpected Death in Epilepsy (SUDEP) in autopsy-negative cases, thrombophilia due to deficiency of natural anti-coagulant factors leading to fatal pulmonary embolism, and aortopathies leading to aortic dissection. The other, is to analyze copy number variants (CNV) which are not routinely analyzed by current bioinformatics pipelines in parallel with analysis of single nucleotide variants (SNV) on the same platform: approximately 5% of disease causing variants are missed due to lack of CNV analysis.
Using our customized 228-gene next-generation sequencing (NGS) testing panel, a high throughput testing workflow, and an improved bioinformatics pipeline, we propose to analyze SNV and CNV in genes for SUND associated conditions. At the case level, we aim to identify the underlying cause of death for a large cohort of SUND cases in the Young (~1500). At the cohort level, we wish to ascertain the utility of testing the 228-gene panel in SUND through statistical analyses and co-segregation studies. This development is built upon over 15 years of experience in postmortem molecular testing and genetic variant interpretation and reporting.
This project will have a direct impact on cause of death determination, further assist at-risk family members with a new human genome analysis tool and innovate genetic variant analysis pipelines. As we evaluate efficiency and utility of the expanded genetic analysis, we will gain a better understanding of the SUND-associated diseases, address the current barrier of uninformative test results, and guide future test development. Additionally, the project provides training opportunities for forensic science graduate students, contributing to the development of a future-focused workforce. Finally, through peer-reviewed publications, this project will further policy decisions in the medicolegal field, as well as impact public health and safety.
This project contains a research and/or development component, as defined in applicable law, and complies with Part 200 Uniform Requirements - 2 CFR 200.210(a)(14).
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