President’s Spotlight—The Molecular Autopsy: A New Tool for Forensic Pathologists

During the year, we will present presidential spotlights for each section to highlight the latest significant research or improvements within its discipline. Examples include cutting-edge technology, standards, or methods that improve the practice. Alternatively, they may show a historical account/timeline of the discipline’s use of innovative technology or research. These are presented to inform all members of how each discipline is responding to the challenges of a modern forensic science world—our theme for the year. This featured submission is from the Pathology/Biology Section.

Sources: Christopher Milroy MD, LLB, Forensic Pathologist, Eastern Ontario Forensic Pathology Unit, and Kathryn C. Pinneri, MD, Director, Montgomery County Forensic Services

A young woman out jogging collapses and dies. A man gets involved in a struggle and dies. In neither case is there an anatomic or toxicological finding to account for the death after autopsy, resulting in an undetermined cause and manner of death. Unfortunately, these types of cases are well recognized by forensic pathologists. The inability to provide answers to surviving family members is extremely frustrating. Recent advances in and the availability of molecular testing provide forensic pathologists with another tool that may identify an underlying genetic vulnerability that could account for the previously undetermined death.

Postmortem genetic testing can now be conducted on autopsy tissue, preferably blood preserved in a purple top (Ethylenediaminetetraacetic Acid [EDTA]) tube, fresh tissue in transport medium, or fresh frozen tissue (such as heart, kidney, or liver). Tissue embedded in paraffin blocks has been used for identification purposes, but the quality of DNA obtained is currently inadequate for disease identification. Disorders of cardiac conduction, such as channelopathies like long QT and Brugada syndromes, are causes of sudden death with no anatomic findings. It is now known that they may have a genetic basis that could be identified through postmortem genetic testing, thus providing a potential cause of death in an otherwise negative autopsy and allowing surviving family members to be screened if deemed appropriate.

While previously too expensive for government-funded, cash-strapped medical examiner and coroner offices, the costs for postmortem genetic testing have greatly decreased, making it a viable option for appropriate cases. Commercial labs now provide this service and offer many different panels testing for a variety of different diseases. For example, panels exist for channelopathies, cardiomyopathies (disorders of heart muscle), vasculopathies, such as for Ehlers-Danlos syndrome, that may predispose to vessel rupture, and coagulopathies, such as Leiden Factor V deficiency, which predisposes to deep vein thrombosis and thus pulmonary thrombo-embolism at a young age. It is also increasingly recognized that conditions such as epilepsy may have an underlying genetic basis and the associated genes can be tested for postmortem. Sudden infant deaths are also an increasing focus of the molecular autopsy.

The ability to identify pathogenic genes is not entirely straightforward. The question faced by the forensic pathologist is what to do with a positive test and what to do with genetic variants of uncertain significance, which are quite common. It is the opinion of some clinicians that genetic testing results should not be placed on death certificates as it can label a family as having a genetic condition, which may create insurance or other problems. So one approach is to provide a copy of the testing results to help determine the need for testing of surviving relatives, but the results are not specifically included in the cause of death. This is the approach being taken by the Ontario Forensic Pathology Service. However, the family is recommended to seek the opinion of an appropriate clinician, such as a cardiologist with an interest in genetics, and electrophysiology in the case of potential channelopathies. Testing of relatives is covered through health care.

At the Montgomery County Forensic Services Department in Montgomery County, TX, postmortem genetic testing has become a frequently used tool to augment the autopsy. It is performed on individuals found to have a potential genetic condition, such as dilated or hypertrophic cardiomyopathy, a hereditary thrombophilia resulting in a pulmonary embolus, some individuals with seizure disorder, and sudden death in the young without an identified anatomic or toxicologic cause of death. Testing is now being expanded to include unexplained sudden deaths in infants. Consent from the legal next of kin is typically obtained and, to date, no family has declined. Costs are covered by the office, and results are communicated with the family members. The results are also reported in the autopsy report and provided to the family members. Familial variant testing for first-degree family members is offered at no cost for all pathogenic variants identified and some variants of uncertain significance. The families referred for this testing have all been very thankful for the option—providing important health information if positive, or a sense of relief if negative. We know of several members in one family who underwent placement of an internal defibrillator for genetic hypertrophic cardiomyopathy that would have gone undetected had the postmortem testing not been performed. Access to genetic counselors is an important aspect of genetic testing and should be part of the process. Fortunately, many commercial labs offer this service with testing at no additional cost.

The molecular autopsy is being increasingly used to provide additional information to the relatives of decedents and is now within the cost capabilities of some medical examiner’s and coroner’s offices or for the relatives to pay for the testing. It is important to keep in mind that molecular testing, like other ancillary tests such as imaging and toxicology, cannot replace the autopsy, and the results must be interpreted in the context of the whole death investigation.