Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths

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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.

Introduction

Sudden unexplained death (SUD) in apparently healthy individuals presents vexing challenges for medical examiners and still remains an important public health priority. SUD is defined by a cause of death which remains unknown after complete autopsies, comprehensive laboratory testing, review of all available history, and performance of a comprehensive scene investigation. According to the Centers for Disease Control and Prevention, more than 4500 infants die suddenly each year in the United States with no immediate or obvious cause of death; half of those deaths remain unexplained after a forensic investigation. Furthermore, the prevalence of sudden unexplained deaths beyond infancy (1ā€“22 years old) is also estimated to be greater than 2000 annually in the United States [1]. Despite a decline in SUD rates over the past decade, the rates are still disproportionately high amongst certain population groups, especially in African Americans and American Indian/Alaska Natives [2].

It is estimated that 10ā€“35% [3], [4], [5], [6], [7], [8] of SUD may be explained by cardiac channelopathies, which affect heart rhythm and cardiac electrical conduction physiology. These disorders comprise of a group of inheritable cardiac arrhythmia syndromes, such as long QT syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome, and short QT syndrome. Despite extensive attempts at developing nationalized standards in SUD investigation including the establishment of basic guidelines [9], [10], currently, wide variation exists across the United States when investigating and certifying SUD [11]. Unfortunately, the use of molecular diagnostics is not commonly made as part of the medical investigation of SUD cases. The situation in European countries is also similar, with the application of genetic testing in routine forensic investigations being very limited [12]. Nevertheless, the New York City (NYC) Office of Chief Medical Examiner (OCME) has routinely integrated molecular testing of six major cardiac channelopathy genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and RyR2) in SUD investigations since 2008. This testing panel is significant for over 80% of the long QT syndromes, 25% of Brugada syndrome, and 50% of catecholaminergic polymorphic ventricular tachycardia (CPVT) [13].

The main goal of this study is to evaluate the significance of cardiac channelopathies in SUD within a large and ethnically diverse population from a single urban medical examiner's office in the United States.

Section snippets

Study cohort

Biological samples from a total of 340 cases of sudden unexpected natural death were submitted to the Molecular Genetics Laboratory in the New York City OCME for cardiac channelopathy testing from 2008 to 2012. Of those cases, 66 cases were excluded from this study based on the following criteria: (1) only an external examination was performed (often due to religious objection to autopsy), and (2) the causes of deaths were explained by autopsy or forensic laboratory findings. Based on this, 274

Unique demographic characteristics of the study cohort

The demographic characteristics of the 274 sudden unexplained deaths (SUD) investigated by the NYC OCME are summarized in Table 1. These 274 cases were divided into two age groups: infants (ā‰¤1 year old, 141 cases) and non-infants (>1 year old, 133 cases). In infants, 92.9% were younger than 6 months. In non-infants, 78.2% were older than 18 years old (the oldest decedent was 58 years old). African American is the leading ethnicity observed in both infants (60.3%) and non-infants (35.3%). While

Discussion

We present data from a comprehensive postmortem evaluation of 274 sudden unexplained deaths in New York City. Here we discuss the unique characteristics of the cohort, principal findings from this study, the benefits of molecular testing to the at-risk family members, and the challenges of the postmortem molecular diagnostics along with the limitations of this study.

Source of funding

This project was partially supported by Awards no. 2009-CD-BX-0049 and 2011-DN-BX-K535, awarded by the National Institute of Justice, Office of Justice Programs, U.S. Department of Justice.

Conflict of interest statement

There is no conflict of interest to be disclosed for any author on this paper.

Acknowledgement

We thank Dr. Jason K. Graham for critical review of this manuscript.

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