Molecular Autopsy for Sudden Death in the Young: Is Data Aggregation the Key?

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 .

Pharmacogenetics and the postmortem molecular autopsy

“…It was discovered that SUD cases carry elevated levels of mitochondrial DNA heteroplasmy (i.e., different copies of the mitochondrial genome) that also was detected in their mothers. These interdisciplinary consortium-based multiomic interrogations of death-related phenotypes are a high-powered approach to dissecting the genetic contribution to SUD etiology (Ackerman et al, 1999;Rueda et al, 2017;Torkamani et al, 2016). intermediate (IM), extensive/normal (EM/NM, largest proportion of the general population), and ultra-rapid (UM, fastest enzyme activity).…”

“…Molecular autopsy exploits several molecular techniques, especially those of genetic nature, to determine the conclusions about cause (CoD) and/or manner of death (MoD) in unexplained cases. Much of the molecular autopsy work to date involves investigation of sudden unexplained deaths (Ackerman, Tester, & Porter, ; Rueda et al, ; Torkamani et al, ) but this article will focus on another application of the molecular autopsy: drug‐related deaths.…”

“…investigation of sudden unexplained deaths (Ackerman, Tester, & Porter, 1999;Rueda et al, 2017;Torkamani et al, 2016) but this article will focus on another application of the molecular autopsy: drug-related deaths.…”

“Donating our bodies to science”: A discussion about autopsy and organ donation in Turner syndrome

“…The highest yield of rare pathogenic mutations is found in families with a history of sudden cardiac death, young persons without detectable physiologic findings on conventional autopsy, women with recurrent fetal demise and families with consanguinity. Causal genetic mutations are found in up to 50% of these cases, and an additional 30% were found to harbor rare genetic variants of uncertain significance that may actually be reclassified as pathogenic mutations over time (Rueda et al, 2017; Shamseldin et al, 2018). Individuals in the general population with similar risk profiles may benefit from genetic screening for early diagnosis and prophylactic therapies (Shanks et al, 2018).…”

Molecular genetic basis of sudden cardiac death in the young with cardiomyopathy of various origins

“…Один из методов, который медленно внедряется в практику судебно-медицинского эксперта, -метод молекулярной аутопсии. Этот метод, в частности, предполагает проведение посмертного генетического исследования на предмет носительства мутантных аллелей в генах-кандидатах наследственной предрасположенности к внезапной смерти, связанной с патологией сердца у лиц молодого возраста [16][17][18][19].…”