title: Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths.
abstract: Sudden unexplained deaths (SUD) in apparently healthy individuals, for which the causes of deaths remained undetermined after comprehensive forensic investigations and autopsy, present vexing challenges to medical examiners and coroners. Cardiac channelopathies, a group of inheritable diseases that primarily affect heart rhythm by altering the cardiac conduction system, have been known as one of the likely causes of SUD. Adhering to the recommendations of including molecular diagnostics of cardiac channelopathies in SUD investigation, the Molecular Genetics Laboratory of the New York City (NYC) Office of Chief Medical Examiner (OCME) has been routinely testing for six major channelopathy genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and RyR2) since 2008. Presented here are the results of cardiac channelopathy testing in 274 well-characterized autopsy negative SUD cases, all with thorough medicolegal death investigation including complete autopsy by NYC OCME between 2008 and 2012. The cohort consisted of 141 infants (92.9% younger than six-month old) and 133 non-infants (78.2% were between 19 and 58 years old). Among the ethnically diverse cohort, African American infants had the highest risks of SUD, and African American non-infants died at significantly younger age (23.7 years old, mean age-at-death) than those of other ethnicities (30.3 years old, mean age-at-death). A total of 22 previously classified cardiac channelopathy-associated variants and 24 novel putative channelopathy-associated variants were detected among the infants (13.5%) and non-infants (19.5%). Most channelopathy-associated variants involved the SCN5A gene (68.4% in infants, 50% in non-infants). We believe this is the first study assessing the role of cardiac channelopathy genes in a large and demographically diverse SUD population drawn from a single urban medical examiner's office in the United States. Our study supports that molecular testing for cardiac channelopathy is a valuable tool in SUD investigations and provides helpful information to medical examiners/coroners seeking cause of death in SUD as well as potentially life-saving information to surviving family members.
authors.affiliation: Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, New York, NY 10016, United States.
authors.forename: Dawei
authors.initials: D
authors.lastname: Wang
authors.affiliation: Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, New York, NY 10016, United States.
authors.forename: Krunal R
authors.initials: KR
authors.lastname: Shah
authors.affiliation: Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, New York, NY 10016, United States.
authors.forename: Sung Yon
authors.initials: SY
authors.lastname: Um
authors.affiliation: Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, New York, NY 10016, United States.
authors.forename: Lucy S
authors.initials: LS
authors.lastname: Eng
authors.affiliation: Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, New York, NY 10016, United States.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, New York, NY 10016, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Forensic Biology Department, New York City Office of Chief Medical Examiner, New York, NY 10016, United States.
authors.forename: Adele A
authors.initials: AA
authors.lastname: Mitchell
authors.affiliation: Forensic Pathology Department, New York City Office of Chief Medical Examiner, New York, NY 10016, United States.
authors.forename: Leze
authors.initials: L
authors.lastname: Nicaj
authors.affiliation: Formerly Forensic Biology Department, New York City Office of Chief Medical Examiner, New York, NY 10016, United States.
authors.forename: Mechthild
authors.initials: M
authors.lastname: Prinz
authors.affiliation: Departments of Medicine (Cardiology) & Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Ave. Bronx, NY 10461, United States.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: McDonald
authors.affiliation: Forensic Pathology Department, New York City Office of Chief Medical Examiner, New York, NY 10016, United States.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Sampson
authors.affiliation: Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, New York, NY 10016, United States. Electronic address: ytang@ocme.nyc.gov.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Tang
mesh_terms: D000293:Adolescent; D000328:Adult; D053447:Channelopathies / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D016757:Death, Sudden, Cardiac / Q000453:epidemiology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D044469:Racial Groups / Q000235:genetics; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D014481:United States / Q000453:epidemiology; D055815:Young Adult
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C489622:KCNE1 protein, human; C489619:KCNE2 protein, human; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; D062554:NAV1.5 Voltage-Gated Sodium Channel; D024642:Potassium Channels, Voltage-Gated; D019837:Ryanodine Receptor Calcium Release Channel; C568320:SCN5A protein, human
keywords: Arrhythmia; Epidemiology; Genetics testing; Ion channels; Sudden death