Changing times: DNA resequencing and the “nearly normal autopsy”

Abstract 

No matter how meticulous the autopsy, non-traumatic deaths in the young go unexplained from 5–10% of the time. The percentage is higher in children and young adults. Advances in molecular biology and DNA technology now make it possible to explain many of those deaths. This development is not without irony. At the same time that many clinicians are expressing frustration about the lack of tangible gains provided by the Human Genome Project [Greenhalgh T. The Human Genome Project. J R Soc Med. Dec 2005;98(12):545], and pathologists are wondering about the viability of their field, DNA technology is about to reshape the field of forensic pathology. Emerging evidence suggests that the underlying cause of death in many is genetic, and that both the heart and liver abnormalities can both play a role. The problem is that death from a wide variety of genetic defects may leave no histological markers. The ability to identify these “invisible diseases” with postmortem genetic testing has become a reality far more quickly than anyone had ever imagined. The US Food and Drug Administration is about to place “black box” warnings on warfarin advising doctors screen potential recipients for the ability to metabolize that drug and the American Heart Association has recently editorialized that because of genetic-induced variations in electrical conduction that all newborns should have a screening electrocardiogram before they leave the hospital. The introduction of large-scale genetic screening will have an enormous effect on the practice of forensic pathology, far beyond anything seen in our lifetimes. It will also change the practice of medicine as we know it. This paper reviews the current status of the problem.

Keywords: Sudden cardiac death, Normal autopsy, Hypertrophic cardiomyopathy, LQTS, P450 polymorphism, Drug death, DNA array, Ryanodine