Significant efforts have already focused on evaluating postmortem DNA samples.56–69,84 Although there is near-universal consensus that saving a genetic sample from the decedent is the best practice, there are several hurdles to overcome These hurdles include the variability in practice among coroners and medical examiners’ offices, the understandable desire of the family to have the body released back to their care for burial as soon as possible, the degradation of DNA in postmortem samples prior to collection, and the practical considerations of getting material saved, stored, and DNA extracted effectively.85–88 Table 89.3 tabulates the yield of postmortem genetic screening after sudden unexplained death There continues to be discussion within the field about the best genetic approach Some studies performed genetic screening panels using a small, predetermined list of genes firmly implicated in sudden death.58,59,69 Others have used whole exome or whole genome sequencing, to sample more broadly across the genome, using computational tools to evaluate 100 or more genes.55,57,89 As costs of next-generation sequencing decrease, the latter approach is likely to be increasingly available However, the risk of larger panels is the discovery of variants of unknown significance or variants in genes with unclear application to the case at hand Table 89.3 Yield of Pathogenic and Likely Pathogenic Variants in Molecular Autopsy Studies First Author, Year, Reference Number Methner, 201691 Winkel, 201254 Lahrouchi, 201770 Skinner, 201164 Chugh, 200458 Farrugia, 201560 Wang, 201468 Di Paolo, 200459 Behr, 200892 Tester, 201266 Bagnall, 201653 Nunn, 201589 Anderson, 201655 Christiansen, 201657 Number of Genes Screened 64 77 5 23 11 131a 135 100 100 Number of Probands 71 44 302 52 12 16 274 10 57 173 490 59 32 61 Yield of Pathogenic and Likely Pathogenic Variants (%) 3.7 11 13 15 16 19 20 20 21 26 27 29 32 34 aThe number of genes tested varied within the study Definitions of sudden unexplained death were extracted from each paper and were independently reclassified as sudden unexplained death or sudden arrhythmic death, but no trend exists between the definitions and the yield of variants, so they are listed sequentially by yield, not by definition Interpretation of genetic information can be exceptionally difficult in sudden unexplained death cases A recent study in 302 sudden arrhythmic death cases that searched specifically for clinically actionable pathogenic or likely pathogenic variants found that molecular autopsy combined with clinical evaluation increased the diagnostic yield in surviving families from 26% to 39%.70 Families should be forewarned before molecular autopsy is undertaken that genetic information is additive and rarely diagnostic in isolation In summary, genetic sequencing and interpretation is a parallel process that informs phenotypic workup, but does not replace it As Fig 89.1 shows, molecular autopsy can be performed simultaneously with the family's phenotypic workup, using genetic information to guide the workup as necessary, but incorporating phenotypic information to make a final diagnosis in the family From there, clinicians can determine the value of lifestyle modifications, pharmacotherapy, interventional therapy, and family cascade screening Ethical Considerations and Future Directions (See Also Chapter 83) Families require careful counseling prior to genetic screening after a sudden death episode Despite everyone's best intentions, there are potential downsides to testing surviving family members for a genetic variant that is found in the decedent In the United States, federal law (the Genetic Information Nondiscrimination Act) prohibits discrimination by health insurance companies, group health plans, employers, labor unions, and employment agencies on the basis of genetic testing information This law does not protect against use of genetic testing information by companies that sell life insurance, disability insurance, or long-term care insurance In addition, while the decedent's insurance will occasionally cover the cost of molecular autopsy, this is not universal, and providers should be transparent with families about the out-ofpocket costs of molecular autopsy prior to proceeding.90–92 Screening for Atherosclerotic Cardiovascular Disease Risk Factors The chronic process of atherosclerosis begins in early life, with initial changes observed even in the fetus.93 In two contemporary studies, Pathological Determinants of Atherosclerosis in Youth94 and the Bogalusa Heart Study,95 autopsies of youth who died from unintentional injury revealed that the severity and extent of atherosclerosis in childhood correlated strongly with the presence and intensity of traditional risk factors such as dyslipidemia, hypertension, obesity, tobacco smoke exposure, and diabetes mellitus Multiple observational studies indicate that risk factors measured in childhood predict subclinical atherosclerosis in adulthood, often more strongly than do risk factors96 measured in adulthood Finally, the Princeton Lipid Research Clinics Follow-up Study demonstrated that the metabolic syndrome risk factor cluster in childhood predicted actual clinical cardiovascular disease at ages 30 to 48 years.97 Taken together, these observations create a strong chain of evidence linking risk factor development in early childhood to atherosclerotic cardiovascular disease in adulthood Nevertheless, because of the long period between childhood and adult events, there are no randomized controlled trials of childhood screening for risk factors to reduce adult clinical atherosclerotic cardiovascular disease events Such trials are unlikely to ever occur For this reason, there has been some debate in the medical community about the utility and cost-effectiveness of screening, particularly regarding dyslipidemia This will be reviewed below Of the traditional risk factors for atherosclerotic cardiovascular disease, only dyslipidemia screening will be discussed here While very important, screening for the remainder of the risk factors generally occurs in the primary care clinic, with most centers referring patients with these risk factors to noncardiology specialists (nephrology for hypertension, endocrinology for diabetes, weight management clinic for obesity) when required for management An excellent review of the evidence and expert recommendations for screening for these risk factors in childhood can be found in the 2011 National Heart, Lung, and Blood Institute (NHLBI) Integrated Guidelines for Cardiovascular Risk Reduction in Children.98 ... for the remainder of the risk factors generally occurs in the primary care clinic, with most centers referring patients with these risk factors to noncardiology specialists (nephrology for hypertension, endocrinology for diabetes, weight management clinic for obesity) when required for management