Confirmation of cause and manner of death via a comprehensive cardiac autopsy including whole exome next-generation sequencing.

Abstract

Annually, the sudden death of thousands of young people remains inadequately explained despite medicolegal investigation. Postmortem genetic testing for channelopathies/cardiomyopathies may illuminate a potential cardiac mechanism and establish a more accurate cause and manner of death and provide an actionable genetic marker to test surviving family members who may be at risk for a fatal arrhythmia. Whole exome sequencing allows for simultaneous genetic interrogation of an individual's entire estimated library of approximately 30000 genes. Following an inconclusive autopsy, whole exome sequencing and gene-specific surveillance of all known major cardiac channelopathy/cardiomyopathy genes (90 total) were performed on autopsy blood-derived genomic DNA from a previously healthy 16-year-old adolescent female found deceased in her bedroom. Whole exome sequencing analysis revealed a R249Q-MYH7 mutation associated previously with familial hypertrophic cardiomyopathy, sudden death, and impaired β-myosin heavy chain (MHC-β) actin-translocating and actin-activated ATPase (adenosine triphosphatase) activity. Whole exome sequencing may be an efficient and cost-effective approach to incorporate molecular studies into the conventional postmortem examination.

• Authors: Christina G Loporcaro, David J Tester, Joseph J Maleszewski, Teresa Kruisselbrink, Michael J Ackerman
• Journal: Archives of pathology & laboratory medicine (Arch Pathol Lab Med) Vol. 138 Issue 8 Pg. 1083-9 (Aug 2014) ISSN: 1543-2165 [Electronic] United States
• PMID: 24298987 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MYH7 protein, human
• DNA
• Cardiac Myosins
• Myosin Heavy Chains

Topics

• Adolescent
• Amino Acid Substitution
• Autopsy
• Cardiac Myosins (genetics, metabolism)
• Cardiomyopathy, Hypertrophic, Familial (genetics, metabolism, pathology, physiopathology)
• Cause of Death
• DNA (chemistry, metabolism)
• Death, Sudden (etiology)
• Exome
• Female
• High-Throughput Nucleotide Sequencing
• Humans
• Mutation
• Myocardium (metabolism, pathology)
• Myosin Heavy Chains (genetics, metabolism)
• Sequence Analysis, DNA