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Genetic Variants Linked to Sudden Unexplained Deaths

Researchers improve molecular autopsy accuracy by identifying more genetic variants that could lead to sudden unexplained deaths. These genetic clues may better inform criminal investigations and help prevent deaths in surviving family members.
Date Published
May 17, 2021

Sudden unexplained deaths in infants and adults leave behind devastated family members and frustrated medical examiners. The inability to confidently determine the cause of death is not only hard on the family, it can also lead to false murder convictions.

Advances in molecular genetics have helped scientists to identify genetic variants that may contribute to these mysterious deaths. However, a research team from the City of New York, Office of Chief Medical Examiner reports that molecular autopsies only find genetic links in 10% to 15% of cases of sudden unexplained deaths they review, leaving most cases unresolved.[1]

With support from the National Institute of Justice, these researchers aimed to improve molecular autopsy accuracy by identifying more genetic variants that could lead to sudden unexplained deaths. Specifically, the researchers looked at gene frequency to classify — or, in some cases, reclassify — variants of 89 heart disease genes as disease-causing or harmless, and to identify variants of uncertain significance for further study.

The researchers say findings from this project are a step forward in improving gene variant classification in molecular autopsies that will better inform criminal investigations and advance preventive medicine for families affected by genetically linked sudden deaths.

Reclassifying Genetic Variants

For this project, principal investigator Yingying Tang, a molecular geneticist, collaborated with medical examiners at the City of New York, Office of Chief Medical Examiner. The office’s jurisdiction comprises a large and diverse population that offers a high number of sudden, unexplained death cases that gave the study statistical power (a higher probability of detecting an effect).

Tang and the laboratory scientists identified 296 sudden, unexplained death cases from their office jurisdiction with negative or unremarkable standard forensic investigations from 2001 to 2014 with the following demographics:

Ethnicity:

  • 147 Black
  • 64 Hispanic
  • 49 White
  • 22 Asian
  • 14 mixed ethnicities

Age:

  • 142 infants
  • 39 children
  • 74 young adults
  • 41 adults

The research team extracted DNA from each of the 296 decedents’ postmortem tissue samples or bloodstain cards. They then tested the samples for 89 heart disease genes and confirmed the presence of known genetic variants as disease-causing, of unknown significance, or harmless. These classifications came from a public online archive called ClinVar that contains interpretations of clinically relevant genetic variants.[2]

Next, the researchers applied a statistically robust framework[3] to calculate the frequency of cardiac disease gene variants in the decedents’ DNA. High-frequency variants — variants that appear often in a population — are not likely to cause a disease (harmless), while low-frequency variants — variants that rarely appear in a population — are more likely to cause a disease.

The researchers compared the framework results to the ClinVar database and were able to downgrade 12 genetic variants classified as disease-causing in ClinVar to harmless because they appeared frequently in their jurisdiction’s study subjects.

In addition to reclassifying 12 variants as harmless, the researchers identified 24 disease-causing variants, 41 new variants of uncertain significance, and 124 rare variants of uncertain significance.

The researchers also note that the genetic variant distribution differed by ethnicity for their study subjects, highlighting a “critical need for more studies of ethnic minorities in future population genetic and clinical research, both for more ethnicity matched normative controls … [and] for the creation of clinical guidelines in the current personalized medicine climate that can span all ethnicities.”

Next Steps

Tang and her colleagues plan to use additional support from the National Institute of Justice to further study genetic variants of unknown significance through a collaboration with New York University. They also hope to expand their cardiac testing panel to include genes for epilepsy and disorders of the aorta.  

Ultimately, the researchers hope their work will help law enforcement and medical examiners better determine the cause and manner of death in sudden unexplained death cases.

About this Article

The research described in this article was funded by NIJ grant 2011-DN-BX-K535, awarded to the City of New York, Office of Chief Medical Examiner, New York, New York. This article is based on the grantee final report “Investigating Unexplained Deaths through Molecular Autopsies” (May 2017) by Yingying Tang.

Date Created: May 17, 2021