Molecular Autopsy Becoming Viable to Implement

Molecular autopsies are becoming technically and financially feasible for cases of sudden death (SD) with inconclusive autopsy results, according to a study published July 19 in Genome Research by the Harris County (Texas) medical examiner’s office. Experts say molecular tools will become the standard of care for medical examiners and coroner’s offices investigating SD in infants, children, and young adults.

Heritable genetic variants, including cardiac channel-associated gene variants, are thought to be a cause of up to one-third of SD in young people, but thousands of these cases are assigned an undetermined cause of death due to a lack of definitive autopsy findings. Elucidation of genetic variants responsible for SD can help to establish cause of death and to determine whether familial genetic testing should be considered. However, up until now, postmortem screenings have not been technically or financially viable for most county medical examiners and coroners.

“The work presented here highlights a transition between research and specific clinical cases to implementation of the molecular autopsy as a cost-effective standard of care in postmortem examinations,” writes D. Nicole R. Methner, Ph.D., from the Harris County Institute of Forensic Science in Houston. “By targeting selected exons, cost was kept below $600 per sample.”

The researchers sequenced full exons of 64 genes identified through the literature to be associated with SD (cardiac and non-cardiac causes) in 351 infant and young SD decedents (80.7 percent under one year of age). Mass parallel sequencing relied on a custom gene target exon capture array. The researchers acknowledge that targeted sequencing (versus whole exome sequencing) may miss some potentially deleterious variations, but can yield high coverage while remaining cost-effective.

The researchers found that 77 unique single nucleotide variants were detected in 29 genes. Thirteen individuals (eight infants and five children/young adults) had a reportable genetic variant—likely contributing to the cause of death. This yield (3.7 percent) was substantially lower than previously published reports that found up to one-third of SD cases were due to genetic variations. The authors attribute this difference in diagnostic yield to cohort composition, genetic screening method, or interpretation of genetic testing results. They acknowledge more “restrictive” cohort selection—phenotype- or family history-guided testing —may affect results.

“A crucially important and unique aspect of this approach was the development of a multidisciplinary and multi-institutional panel of experts with expertise in clinical and basic science cardiology, genetics and pathology to review each case for putatively significant genetic variants,” the authors write. “This approach can also be adopted by other medical examiner offices as a tool to initiate molecular autopsy programs as NGS becomes more widely available and the field continually evolves.”

Takeaway: Molecular autopsies are expected to become routine in certain death investigations. However, the benefits of targeted versus broader sequencing approaches should be evaluated in the development of molecular autopsies by weighing the tradeoff between costs and diagnostic yield.