Abstract
The Scripps molecular autopsy study seeks to incorporate genetic testing into the postmortem examination of cases of sudden death in the young (<45 years old). Here, we describe the results from the first 2 years of the study, which consisted of whole exome sequencing (WES) of a cohort of 50 cases predominantly from San Diego County. Apart from the individual description of cases, we analyzed the data at the cohort-level, which brought new perspectives on the genetic causes of sudden death. We investigated the advantages and disadvantages of using WES compared to a gene panel for cardiac disease (usually the first genetic test used by medical examiners). In an attempt to connect complex clinical phenotypes with genotypes, we classified samples by their genetic fingerprint. Finally, we studied the benefits of analyzing the mitochondrial DNA genome. In this regard, we found that half of the cases clinically diagnosed as sudden infant death syndrome had an increased ratio of heteroplasmic variants, and that the variants were also present in the mothers. We believe that community-based data aggregation and sharing will eventually lead to an improved classification of variants. Allele frequencies for the all cases can be accessed via our genomics browser at https://genomics.scripps.edu/browser.
Highlights
More than 10,000 individuals under the age of 45 years die suddenly and unexpectedly in the USA each year [1]
Individuals between birth and 45 years of age presenting with sudden unexpected death or sudden unexplained death etiology were eligible for enrollment
From August 2014 to March 2017, we compiled 50 cases, with ages ranging from 2 months to 44 years (Table 1; Table S1 in Supplementary Material), of which 19 were females and 31 were males (1:2 ratio)
Summary
More than 10,000 individuals under the age of 45 years die suddenly and unexpectedly in the USA each year [1]. Many of the underlying causes of SDY are hereditary, a postmortem genetic diagnosis [molecular autopsy (MA)] provides a landmark for both the identification of the cause of death and Molecular Autopsy a potential resolution of the uncertainty for risk to living relatives [8,9,10,11,12,13]. In this regard, minimally invasive molecular tests, enabled by recent technological advances in high-throughput DNA sequencing, have reduced the cost of genomic sequencing relative to the gene panel-based tests traditionally available to medical examiners [14,15,16,17]. The MA represents an exciting opportunity to fill in or supplement the knowledge gaps from traditional clinical autopsies while potentially providing accurate genetic information that could facilitate prevention—especially in cases of SDY [6, 18,19,20,21,22,23,24,25,26,27,28]
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