This is the Final Technical Report on a project that developed a statistical framework that was applied in classifying the variants identified through panel testing of cardiac arrhythmogenic genes in a large demographically diverse cohort of sudden unexplained deaths (SUD), which are defined as "natural death in a previously healthy individual whose cause remains undetermined after scene investigation, complete autopsy, and medical record review."
The project used a statistical framework of "high resolution" variant interpretation, accounting for disease inheritance mode, prevalence, allelic heterogeneity, and reduced penetrance, which helped to determine the maximum tolerated allele count (AC) in ExAC for a likely disease-contributing variant. This framework removed two-thirds of variants from consideration compared to the lenient frequency of 0.1 percent for autosomal dominant diseases, without discarding true pathogenic variants that would have been missed if filtering for singleton variants exclusively. This statistical framework was used in classifying the variants identified through panel testing of cardiac arrhythmogenic genes in a large demographically diverse cohort in which all cases underwent comprehensive, standardized investigation in the United States' largest office of chief medical examiner. Applying maximum tolerated reference AC in gnomAD, which contains 277264 sequenced chromosomes, the project reclassified those high AC variants that are currently called mostly as "pathogenic" in ClinVar. Combining literature review, the researchers classified pathogenic variants, novel, and rare variants of uncertain significance (VUS) in the cohort. This report presents the demographic variations of testing yields in the cohort and emphasizes the importance of conducting additional research on novel and rare VUS identified in under-represented populations. 4 tables, 2 figures, and 18 references