Advances in Sequencing Could Transform the Clinical Autopsy

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Next-generation sequencing (NGS) could provide additional insights and medical value to post-mortem examinations. The widely observed decline in autopsies is largely a result of the decline in disease-related autopsies, which represent the majority of all autopsies performed. The medical utility of autopsies related to disease particularly remain in question with declining reimbursement and family consent, but could be reevaluated with the addition of molecular technologies. With NGS, clinical post-mortem examinations stand to reveal more than ever regarding disease-related mortality. Post-mortem sequencing introduces a new paradigm to patient engagement with important ethical questions, but also represents a minimally tapped resource for family health and potentially even translational research.

Autopsy rates have declined significantly over the past several decades, both in the United States and abroad, across autopsies performed at the request of surviving family (clinical) or for academic and institutional reasons.  In the United States, the share of hospital deaths with a performed autopsy has fallen from around 50% in 1970 to approximately 5%. The National Center for Health Statistics (NCHS) has estimated that autopsies were performed for nearly 20% of U.S. deaths until the 1970s and have fallen to 9% or less. Interestingly, rates of autopsy have risen since the 1970s for deaths from external and ill-defined causes, but have only marginally offset declines in autopsied deaths from disease. Deaths from disease are now autopsied less than 5% of the time in the United States.

In the United States, sequencing performed as part of a clinical autopsy could play a role in approximately 11,000 cases a year of sudden unexplained death in individuals under 45. The use of sequencing in clinical autopsies is far from systematic, but is commonly deployed to detect mutations affecting cardiac function, particularly electrical disorders. Medical examiners’ use of sequencing has been possible through significant cost improvements to the technology, particularly when performed on targeted panels or for whole exomes.

The current use of molecular diagnostics in the investigation of sudden unexplained deaths began with post-mortem PCR testing of KVLQT1 gene mutations in a 19-year-old who died unexpectedly after a near drowning. Molecular autopsies have since shifted to NGS targeted panels for 4 of the most common mutations related to arrhythmia and heart disorders as well as whole exome sequencing runs that reveal additional less common, putative biomarker genes.

The Scripps Research Institute has been a research leader in molecular autopsies. Scripps researchers recruited families that had experienced sudden cardiac deaths to perform post-mortem sequencing on 25 individuals. Genetic causes of death were identified in 4 cases and plausible causes of death in another 6. Other larger studies determined similar rates of discovery. Yet another study limited to exertion-related sudden unexplained deaths in individuals 19 years and younger found putative mutation biomarkers in 30% of cases using targeted panels and in another 14% with subsequent whole exome sequencing.

While sudden cardiac death has been the predominant target of molecular autopsies, also promising is post-mortem sequencing in cases of unexpected or sudden infant death. Targeted and exome sequencing could be used to reveal inherited diseases, particularly metabolic disorders.

Post-mortem sequencing as part of clinical autopsies represents a notable facet of rising consumer and patient engagement with sequencing technology. In studies such as the one conducted by Scripps, some family members were also tested to determine whether they carried the same mutation. Some studies have relied more extensively on testing of surviving family to identify causes of sudden cardiac death. Provided with the knowledge of genetic risk, surviving family members made precautions regarding exertion and sought medical intervention such as preemptive implantation of defibrillators. However, significant ambiguity remains in the majority of sudden death cases that precludes definite attribution to genetic roots. Some family members worked to address genetic mutations later found to have a weaker association with the cause of sudden death.

The utility of post-mortem sequencing is likely to improve with higher usage among medical examiners and healthcare professionals. Ambiguity regarding the role of mutations in sudden death can be mitigated and targeted sequencing panels refined through the wider collection and sharing of genomic and family history data from molecular autopsies. Autopsy data may also provide key insights into disease pathology useful to translational medicine.

The National Association of Medical Examiners already recommends the preservation of tissue samples from autopsies without formalin in order to use them as a later resource for post-mortem sequencing. The clinical sequencing clients of the future, hospital labs, may also in the future be candidates to implement molecular autopsies for inpatient deaths. The potential of post-mortem sequencing is also based on the public’s rising exposure to sequencing through clinical care and direct-to-consumer testing services for health and ancestry. The development of potentially less invasive autopsy procedures that recover samples for sequencing coupled with clearly demonstrated benefits to family health may create yet another application market for sequencing.