title: 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.affiliation: From the Mayo Medical School, Rochester, Minnesota (Ms Loporcaro); the Departments of Internal Medicine/Division of Cardiovascular Diseases (Mr Tester and Dr Ackerman), Laboratory Medicine & Pathology, Division of Anatomic Pathology (Dr Maleszewski), Laboratory Medicine & Pathology, Division of Laboratory Genetics (Ms Kruisselbrink), Molecular Pharmacology & Experimental Therapeutics (Dr Ackerman), and Pediatric and Adolescent Medicine/Division of Pediatric Cardiology (Dr Ackerman), and the Windland Smith Rice Sudden Death Genomics Laboratory (Mr Tester and Dr Ackerman), Mayo Clinic, Rochester, Minnesota.
authors.forename: Christina G
authors.initials: CG
authors.lastname: Loporcaro
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Maleszewski
authors.forename: Teresa
authors.initials: T
authors.lastname: Kruisselbrink
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
mesh_terms: D000293:Adolescent; D019943:Amino Acid Substitution; D001344:Autopsy; D024722:Cardiac Myosins / Q000235:genetics* / Q000378:metabolism; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002423:Cause of Death; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D003645:Death, Sudden / Q000209:etiology; D059472:Exome; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D018995:Myosin Heavy Chains / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: C501641:MYH7 protein, human; D004247:DNA; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains