Forensic Pathology and Heritable Cardiovascular Disease: Room for Growth

In most areas of the United States, the sudden and unexpected death of a previously healthy person falls under the jurisdiction of a forensic pathologist. Forensic pathologists are therefore often in a position to diagnose a multitude of potentially heritable diseases including cardiomyopathies, channelopathies, and aortopathies. Importantly, these conditions can remain clinically undetected until lethal complications occur—for example, a cardiac arrhythmia or an aortic dissection—and the first chance for diagnosis may come at autopsy.  While finding a genetic diagnosis at this stage obviously comes too late for our patient, it affords families the chance to seek diagnosis and proactive treatment. If we identify a causative mutation, cascade testing of family members can identify those who are at risk and those. This information can also give peace of mind to family members who do not carry the gene and allow them to safely forgo follow-up screening.

Despite the potential benefits of postmortem genetic testing, there are many obstacles which have prevented routine implementation. One of the main barriers is cost. Insurance companies do not reimburse for postmortem genetic tests, and while the affordability has improved, a single panel (testing multiple genes at once) typically costs hundreds of dollars. If expanded testing (whole exome or whole genome) is needed, the cost is even greater.  Medical Examiner and Coroner offices are funded by local or state governments and have limited resources which are typically strained by high rates of homicides and overdoses. On such tight budgets, the occasional genetic test may be pursued – one or two a year, perhaps – but more regular testing is out of reach. Some families are willing and able to pay for genetic testing, but many cannot afford the cost.

Additional challenges can arise when interpreting the results of genetic testing, which are more complex than a simple ‘positive’ or ‘negative’ result. The classification of cardiovascular gene variants as either benign (normally found in the population) or pathogenic (causative of disease) is more challenging than the classification of cancer-related genes, and many fall in the indeterminate category of ‘VUS’ – a variant of uncertain significance.  Typically, in clinical settings when the patient is still alive, a genetic counselor helps the family interpret the findings. With a “VUS”, they may help coordinate further testing of family members to identify whether the variant shows an association with the disease phenotype; they can also be a point of contact if genetic variants are reclassified as more data becomes available. Having the input of a clinician is imperative because family members need phenotypic screening as well – by CT or MRI scans, echocardiogram, electrocardiogram, and/or other modalities – as the yield of postmortem genetic testing is far from 100%, even for disorders that show clear autosomal dominant inheritance patterns.

Some medical examiner offices have successfully developed regional systems to ensure that decedent’s families receive coordinated care in the event a heritable cardiovascular disease is suspected. These systems are multidisciplinary and include the forensic pathologists, genetic counselors, cardiologists, and specialists in connective tissue disease, and are often informally built networks of clinicians with a common goal. While this is an excellent way to care for families, the majority of the United States lacks such coverage because of regional variation in death investigation and access to medical specialists. Even in the face of these limitations, forensic pathologists can have a huge impact by simply recognizing the potential for genetic disease and saving a sample for possible testing. Genetic testing is expensive and complex, but a phone call to a next-of-kin is cheap and straightforward. Freezing a sodium-EDTA tube of whole blood is also relatively inexpensive, yet preserves an otherwise irretrievable sample. Notifying families of their potential risk for disease, and encouraging them to seek medical diagnosis and treatment, provides a forensic pathologist the opportunity to potentially save lives—a rarity in our field.

-Alison Krywanczyk, MD, FASCP, is currently a Deputy Medical Examiner at the Cuyahoga County Medical Examiner’s Office.