Office Of Chief Medical Examiner Research Articles

Identification investigations: a collaborative approach to the resolution of long-term unidentified persons cases at the NYC Office of Chief Medical Examiner

Identification investigations: a collaborative approach to the resolution of long-term unidentified persons cases at the NYC Office of Chief Medical Examiner

Case of Complete Hyoid Body Agenesis and the Benefits of Anthropology Consultation When Assessing Structures of the Neck

This case study details a rare finding of hyoid body agenesis. Anthropological consultation on structures of the neck is frequently utilized at the New York City Office of Chief Medical Examiner. This practice allows for anthropology findings to supplement and support the autopsy reports produced by the medical examiners, often detailing the presence of trauma and/or anatomical variants. In this case, while no trauma to the neck was suspected, anthropological consultation revealed a unique hyoid morphology that has not yet been documented in the forensic literature. Moreover, this morphology seems to support a single developmental origin for the hyoid body, which has been theorized in recent embryological research. Analysis of this hyoid body agenesis may contribute meaningful data to discussions regarding hyoid bone developmental origins and provide a useful example for other forensic cases involving similar morphology. This case exemplifies the benefit of pathological and anthropological collaboration in distinguishing between trauma, pathology, and anatomical variants when assessing structures of the neck.

Effects of maceration on light stable isotopic (δ13C, δ18O) values of pig (Sus scrofa) rib bone carbonate

Geoprofiling isotopic analyses provide investigative leads for unidentified human remains cases by determining possible regions of origin or excluding unlikely residences during life, which in turn can reduce the number of missing persons an investigator mustconsider. However, maceration methods involving heat, bleach, baking soda, and detergents have much potential to significantly change biogenic isotopic values in the structural carbonate phase of bone bioapatite. Here we test the impact of seven maceration methods on δ13C and δ18O values of bone carbonate (BC) of pig (Sus scrofa) ribs. Four of the seven maceration methods altered pig δ13CBC values with offsets ranging from 0.4‰ to 1.4‰; this amount of change would not severely impact human diet or geolocation interpretations. Five of the methods significantly decreased pig δ18OBC values by averages ranging between 1.0‰ and 2.6‰ likely due to the isotopic exchange between bone and heated water. As an illustrative exercise, we compared our study’s results to macerated rib δ13CBC and δ18OBC values of an identified New York City resident previously in the custody of the New York City Office of Chief Medical Examiner (NYC OCME). We suggest that maceration methods, especially those involving heated water, can potentially contribute to erroneous geolocation estimates garnered from rib δ18OBC values of unidentified individuals.

The neuropathology of intimate partner violence

Lifelong brain health consequences of traumatic brain injury (TBI) include the risk of neurodegenerative disease. Up to one-third of women experience intimate partner violence (IPV) in their lifetime, often with TBI, yet remarkably little is known about the range of autopsy neuropathologies encountered in IPV. We report a prospectively accrued case series from a single institution, the New York City Office of Chief Medical Examiner, evaluated in partnership with the Brain Injury Research Center of Mount Sinai, using a multimodal protocol comprising clinical history review, ex vivo imaging in a small subset, and comprehensive neuropathological assessment by established consensus protocols. Fourteen brains were obtained over 2 years from women with documented IPV (aged 3rd–8th decade; median, 4th) and complex histories including prior TBI in 6, nonfatal strangulation in 4, cerebrovascular, neurological, and/or psychiatric conditions in 13, and epilepsy in 7. At autopsy, all had TBI stigmata (old and/or recent). In addition, white matter regions vulnerable to diffuse axonal injury showed perivascular and parenchymal iron deposition and microgliosis in some subjects. Six cases had evidence of cerebrovascular disease (lacunes and/or chronic infarcts). Regarding neurodegenerative disease pathologies, Alzheimer disease neuropathologic change was present in a single case (8th decade), with no chronic traumatic encephalopathy neuropathologic change (CTE-NC) identified in any. Findings from this initial series then prompted similar exploration in an expanded case series of 70 archival IPV cases (aged 2nd–9th decade; median, 4th) accrued from multiple international institutions. In this secondary case series, we again found evidence of vascular and white matter pathologies. However, only limited neurodegenerative proteinopathies were encountered in the oldest subjects, none meeting consensus criteria for CTE-NC. These observations from this descriptive exploratory study reinforce a need to consider broad co-morbid and neuropathological substrates contributing to brain health outcomes in the context of IPV, some of which may be potentially modifiable.

Training, Deployment Preparation, andBehavioral Health ofNew York National Guard Personnel Deployed to Assist with COVID-19 Decedent Work.

A small body of research conducted mostly among civilians has shown that adequate training and preparation can prevent or reduce the development of behavioral health problems in first responders. Several civilian studies have shown that social support is protective against behavioral health problems. However, very few studies have examined the impact of these factors on the behavioral health of military first responders. Military first responders, who serve in the aftermath of natural disasters and disease outbreaks such as the coronavirus disease 2019 (COVID-19) pandemic, are often members of the National Guard (NG). The purpose of this study was to examine the impact of mortuary affairs training/handling human remains, role preparation, equipment preparation, and unit social support provided to families on the behavioral health of New York (NY) NG personnel deployed to assist the NY Office of Chief Medical Examiner with handling the remains of COVID-19 decedents. We invited 410 NYNG personnel who deployed for the Office of Chief Medical Examiner mission to complete an anonymous online questionnaire 3 to 6 months post-mission. Of the 158 participants, we used the data of the 141 participants who provided consent. Standard behavioral health measures (depression, anxiety, post-traumatic stress disorder, alcohol misuse, and insomnia) as well as study-specific items designed to understand the unique dynamics of this deployment were included. Hierarchical logistic regression analysis was used to examine the relationships between mortuary training, role preparation, equipment preparation, and unit support with behavioral health. Close to two-thirds of the sample reported that they had not been trained in mortuary affairs/handling human remains before the mission. We also found that that lower levels of role preparation and unit support provided to the service members' families increased the odds of meeting criteria for one or more behavioral health problems, but that training in mortuary affairs and equipment preparation was unrelated to behavioral health. Our research points to the importance of emotionally and cognitively preparing service members for the specific dynamics of a deployment and the roles that that they are expected to play. Furthermore, it suggests that supporting the families of NG personnel during domestic missions can benefit the behavioral health of the NG personnel. Additional research is needed to corroborate these findings, particularly the impact of unit support provided to family members on service members' behavioral health.

Molecular genetic characterization of sudden deaths due to thoracic aortic dissection or rupture

BackgroundSudden deaths due to thoracic aortic dissection or rupture (TADR) are often investigated by forensic pathologists in the United States. Up to a quarter of reported TADR result from a highly penetrant autosomal dominant single gene variant. Testing genes associated with familial TADR provides an underlying etiology for the cause of death and informs effective sudden death prevention for at-risk family members. At the New York City Office of Chief Medical Examiner (NYC-OCME), TADR cases are routinely tested by the in-house, CAP-accredited Molecular Genetics Laboratory. In this retrospective study, TADR and cardiovascular cases were reviewed to understand the burden of TADR in sudden deaths, value of molecular diagnostic testing in TADR, and genotype-phenotype correlations in a demographically diverse TADR cohort. MethodsBetween July 2019 and June 2022, cases with in-house cardiovascular genetic testing at NYC-OCME were retrospectively reviewed. Twenty genes associated with familial TADR were analyzed using high throughput massive parallel sequencing on postmortem tissues or bloodspot cards. Variant interpretation was conducted according to ACMG/AMP guidelines. ResultsA total of 1078 cases were tested for cardiovascular genetic conditions, of which 34 (3%) had TADR. Eight of those TADR cases had a pathogenic or likely pathogenic variant (P/LPV), 4 had a variant of uncertain significance (VUS), and 22 cases were negative for variants in TADR genes. The molecular diagnostic yield using the TADR subpanel was 23.5%. The genes with the greatest prevalence of P/LPV were FBN1 (6), followed by TGFBR2 (2), TGFBR1 (1), and MYLK (1). Highly penetrant P/LPV in TGFBR2, FBN1, and TGFBR1 were found in TADR individuals who died younger than 34 years old. Two P/LPV in FBN1 were secondary findings unrelated to cause of death. P/LPV in FBN1 included five truncating variants located in the N-terminal domains and one missense variant involved in the disulfide bonds of the EGF-like domain. All P/LPV in TGFBR1 and TGFBR2 were missense or in-frame deletion variants located in the protein kinase catalytic domain. Three variants were first reported in this study. ConclusionsMolecular testing of familial TADR-associated genes is a highly effective tool to identify the genetic cause of TADR sudden deaths and benefits surviving at-risk families.

Spotlight in Plastic Surgery: January 2023.

Spotlight in Plastic Surgery: January 2023.

Genetic screening of relatives of decedents experiencing sudden unexpected death: medical examiner's office referrals to a multi-disciplinary cardiogenetics program.

Currently, no standardized system exists for evaluating and testing at-risk family members of decedents with abnormal post-mortem genetic testing in cases of sudden unexpected death (SUD). The goal of this study was to evaluate the outcomes of referrals made by an urban medical examiner's office to a multi-disciplinary cardiogenetics clinic. Relatives of decedents with pathogenic/likely pathogenic (P/LP) variants or variants of unknown significance (VUS) in genes known to be associated with cardiomyopathies and/or arrhythmias were identified by the New York City Office of Chief Medical Examiner and referred to the Cardiogenetics Clinic at Montefiore Medical Center. Familial referrals of 15 decedents (median 15years, range 2days to 57years) were evaluated. Variants in 13 genes were identified among decedents (9 arrhythmia, 5 cardiomyopathy). P/LP variants were identified in both arrhythmia (RYR2, SCN5A) and cardiomyopathy syndrome (MYBPC3 (2), MYH7) genes. Thirty-two family members were referred, and 14 variants were detected. One pathogenic (MYBPC3) and two likely pathogenic (RYR2, MYH7) mutations were identified. Referral of at-risk family members of decedents who experienced SUD based on informative post-mortem genetic testing for cardiac and genetic evaluation is warranted, as family studies help to reclassify variants and prevent additional sudden death.

Victim identification and body completeness based on last known location at the World Trade Center

This analysis focuses on the identification efforts conducted by the New York City Office of Chief Medical Examiner (NYC OCME) over a 20-year period from September 11, 2001 to September 11, 2021. Due to this unprecedented level of commitment to victim identification, a wealth of data has been collected over the two-decade period and is still being collected as identification efforts are ongoing. The results of this data analysis are not only informative for the World Trade Center (WTC) victims, but may also be instructional for other large-scale, protracted victim identification efforts. Based on available data, most victims are associated with the impact zones and higher in both towers. No correlation was observed in the overall identification rates based on last known location in the buildings, suggesting that location in the towers does not affect the likelihood of a successful identification. There was, however, a significant difference in the body completeness values observed for victims from the upper floors compared to those below the impact zones. The identification rates and body completeness values for victims onboard the two airplanes are significantly different from each other, possibly related to the varying aircraft speeds at the time of impact.

Complex (Multimodality) Suicides in New York City: 2008-2017.

Complex (or multimodality) suicides pose a challenge for forensic pathologists, because they are infrequent and can be mistaken for the more frequent multiple-injury homicides. Complex suicides are suicides in which 2 or more self-inflicted injurious modalities are used. Among all suicides, this specific type has an incidence of 1.5% to 5%. 1 Few publications exist that examined complex suicides, with the largest review discussing only 19 cases. 2,3 To address the need for better characterization of complex suicides, a 10-year retrospective review was conducted of the database of the New York City Office of Chief Medical Examiner. This is the largest case review to date, with 93 complex suicide cases studied and the first American study contributing to this field. Results provide information regarding the demographics of decedents, incidence of mechanisms used, and mechanisms used in series. Results show that in New York City (NYC), complex suicides predominantly include asphyxia, blunt trauma, and drug toxicity. In addition, suicides in NYC occur at a similar incidence to their US national incidence, and demographics of decedents and most common injury mechanisms mirror those of simple suicides in NYC. However, injury mechanisms do not mirror those that are most common nationally. This contrasts with published data and provides a novel insight into suicide modalities in NYC.

Dementia in the Forensic Setting: Diagnoses Obtained Using a Condensed Protocol at the Office of Chief Medical Examiner, New York City.

Individuals with dementia may come to forensic autopsy, partly because of non-natural deaths (e.g. fall-related), and/or concerns of abuse/neglect. At the New York City Office of Chief Medical Examiner (NYC OCME), brains from such cases are submitted for neurodegenerative disease (ND) work-up. Seventy-eight sequential cases were evaluated using a recently published condensed protocol for the NIA-AA guidelines for the neuropathologic assessment of Alzheimer disease (AD), a cost-cutting innovation in diagnostic neuropathology. ND was identified in 74 (94.9%) brains; the most common were AD (n = 41 [52.5%]), primary age-related tauopathy (n = 26 [33.3%]), and Lewy body disease ([LBD], n = 25 [32.1%]). Others included age-related tau astrogliopathy, hippocampal sclerosis of aging, progressive supranuclear palsy, multiple system atrophy, amyotrophic lateral sclerosis, argyrophilic grain disease, and Creutzfeldt-Jakob disease. 26.8% of AD cases involved a non-natural, dementia-related death, versus 40.0% for LBD. Finally, 70 (89.7%) cases had chronic cerebrovascular disease, 53 (67.9%) being moderate-to-severe. We present a diverse distribution of NDs notable for a high rate of diagnoses associated with falls (e.g. LBD), a potential difference from the hospital neuropathology experience. We also report a high burden of cerebrovascular disease in demented individuals seen at the NYC OCME. Finally, we demonstrate that the aforementioned condensed protocol is applicable for a variety of ND diagnoses.

Acute Intoxications Involving Valerylfentanyl Identified at the New York City Office of Chief Medical Examiner

The detection of novel fentanyl analogs in both seized drugs and toxicological specimens has presented a significant challenge to laboratories with respect to identification, sourcing reference drug standards, the time required for method development and ensuring sufficient method sensitivity. The New York City Office of Chief Medical Examiner has included testing for valerylfentanyl as part of a panel of synthetic opioids since May 2017 but did not identify the first valerylfentanyl-positive case until July 2018. Unlike many other illicit fentanyl analogs that were briefly identified before being replaced with a new analog, valerylfentanyl has persisted over time and continues to be identified in New York City acute polydrug intoxications. Since July 2018, a total of 69 cases were identified to be valerylfentanyl positive, but there were no cases where it was the sole intoxicant. Eighty-four percentage of decedents were male, with the majority being Hispanic males (49%) between the ages of 50 and 59 years (39%). The cause of death in all 69 cases involved acute polydrug intoxications, while the manner of death was deemed an accident in 68 cases and undetermined in one case. Concentrations of valerylfentanyl in postmortem blood ranged from <0.10 to 21 ng/mL, with 44.9% (N = 31) of the concentrations at or below the lower limit of quantification (0.10 ng/mL) but above the limit of detection (0.05 ng/mL). Fentanyl was present in 100% of the cases and in higher concentrations (1.6-116 ng/mL). The most common other drug classes detected with valerylfentanyl were other opiates (76.8%), cocaine/metabolites (50.7%), benzodiazepines (29%) and ethanol (21.7%). Valerylfentanyl is a relatively unknown fentanyl analog with limited information in the scientific literature. This study presents the first publication detailing a series of postmortem cases involving valerylfentanyl in acute intoxications and includes key demographic information and femoral blood concentrations for improved interpretation and analysis.

Self-reported levels of occupational stress and wellness in forensic practitioners: Implications for the education and training of the forensic workforce.

While there is extensive research into wellness and mental health risks for police officers and other first responders, a smaller portion of research has considered how forensic practitioners are affected. This study surveyed 211 forensic practitioners from the American Academy of Forensic Sciences membership, the Clark County Office of the Coroner/Medical Examiner, and the New York City Office of Chief Medical Examiner to assess current wellness perceptions within forensics. The 22-question survey focused on (a) how the demands of daily casework affect self-perceived burnout levels, (b) whether mental health issues are adequately addressed during the education and training of the forensic workforce, and (c) whether forensic professionals are getting the wellness support that they themselves feel that they need. Basic descriptive statistics, chi-square (χ2 ) cross tabulations, and correlation analyses were constructed to assess relevant relationships within survey responses. Results indicate that forensic professionals report a high level of burnout and a lack of sufficient wellness resources in their current professional climate. While professionals feel fulfilled from their work, the majority of respondents (73.9%) felt that common mental health issues that exist in their profession were not adequately addressed during their workplace training, academic schooling, or professional certification. Despite the uniformly weak correlations observed between variables, chi-square analyses reveal practically and statistically significant trends that warrant further investigation, particularly in the context of vicarious trauma. Overall, this study provides an important baseline for future wellness research to support the specialized needs of forensic scientists during their training and education.

Hypothermia-related Deaths: A 10-year Retrospective Study of Two Major Metropolitan Cities in the United States.

Hypothermia-related deaths affect vulnerable populations and are preventable. They account for the vast majority of weather-related deaths in the United States. The postmortem diagnosis of hypothermia can be challenging, as there are no pathognomonic signs. The electronic databases of the New York City Office of Chief Medical Examiner and Harris County Institute of Forensic Sciences were searched for all fatalities where the primary cause of death included hypothermia, between January 2009 and July 2019. There were 139 hypothermia deaths in New York City (NYC) with an average annualized rate of 1.7 per million. During this same time, there were 50 hypothermia deaths in Houston with an average annualized rate of 2.4 per million. Males were more likely to die of hypothermia compared to females in both cities. The rate ratio (RR) in NYC was 3.55 (95% CI 2.40, 5.25), while the RR in Houston was 2.83 (95% CI 1.50, 5.32). Age- and sex-specific standardized hypothermia mortality rates were 18.2 (95% CI 15.1, 21.2) per million in NYC and 30.1 (95% CI 21.7, 38.6) per million in Houston. The comparative hypothermia death ratio was 1.66 (95% CI 1.19, 2.30), indicating hypothermia mortality in Houston was 66% higher than in NYC. There was no correlation between zip code poverty rates and hypothermia-related deaths. The most consistent autopsy finding was Wischnewski spots (56.6%), and ethanol was the most common toxicological finding (36.5%). Local agencies can use this data to target these higher-risk populations and offer appropriate interventions to try to prevent these deaths.

Noelle J. Umback

Noelle J. Umback, 50, died on Feb. 15 in Brooklyn, New York. “Noelle was proud of being from small-town South Dakota, and she was always happy to show visitors her hometown of Lemmon. She was equally proud of her adopted home, New York City, and was happy to show anyone the city. After graduation, she joined the Office of Chief Medical Examiner. After the Sept. 11 terrorist attacks, she helped identify remains of victims from their DNA. She led one of the DNA teams and quickly rose through the ranks to criminalist IV. She regularly spoke to groups about being a woman in the science, technology, engineering, and mathematics (STEM) fields. She also had a sense of humor that left many speechless with a barb.”— David E. Lewis, friend and colleague Most recent title: Criminalist IV, New York City Office of Chief Medical Examiner Education: BS, chemistry, South Dakota State

Using postmortem formalin fixed paraffin-embedded tissues for molecular testing of sudden cardiac death: A cautionary tale of utility and limitations

For archived cases of previously young healthy individuals where cause of sudden death remains undetermined, formalin fixed paraffin-embedded tissues (FFPE) samples are often the only biological resource available for molecular testing. We aim to ascertain the validity of postmortem molecular analysis of 95 cardiac genes using the FFPE samples routinely processed in the offices of medical examiners - typical fixation time in formalin ranges from days to months. The study was conducted in the College of American Pathologists accredited Molecular Genetics Laboratory within the City of New York Office of Chief Medical Examiner. Twelve cases, with FFPE samples and corresponding non-formalin fixed samples (RNAlater-preserved tissues or bloodstain card), were chosen for testing results comparison. The methods of extracting DNA from FFPE samples using Covaris, Qiagen, and Promega products showed comparable results. The quality of the extracted DNA, the target-enriched DNA libraries of 95 cardiac genes using HaloPlex Target Enrichment system by Agilent Technologies, and sequencing results using Illumina Miseq instrument were evaluated. Compared to the sequencing results of the nonfixed samples, the FFPE samples were categorized into three groups: 1) Group 1 samples fixed in formalin 2–6 days, had greater than 55 % sequencing regions ≥30x and 94%–100% variant concordance. 2) Group 2 samples fixed in formalin for 8 days, showed intra-sample sequencing variations: the surface tissues showed 25%–27% extra variants (false positive) and 8.1%–9.7% missing variants (false negative), whereas the repeated core tissues showed reduced extra variants to 1.6 % and the false negative error was unchanged. 3) Group 3 samples fixed in formalin 29–136 days, had 2–55 % sequencing regions ≥30x, up to 52.2 % missed variants and up to 6.3 % extra variants. All reportable variants (pathogenic, likely pathogenic or variant of uncertain significance) identified in the nonfixed samples were also identified in FFPE, albeit three variants had low confidence variant calling. In summary, our study showed that postmortem molecular diagnostic testing using FFPE samples routinely processed by the medical examiners should be cautioned, as they are replete with false positive and negative results, particularly when sample fixation time is longer than 8 days. Saving non-formalin fixed samples for high fidelity molecular analysis is strongly encouraged.

Evaluation of 4-fluoroisobutyrylfentanyl in blood samples from 247 authentic cases submitted to the New York City Office of Chief Medical Examiner in 2017–2018

4-Fluoroisobutyrylfentanyl (FIBF) was first identified at the New York City Office of Chief Medical Examiner (OCME) in May 2017 and was reported qualitatively due to the constant changes in “fentalogs” (analogs of fentanyl) identified. However, by the year’s end, FIBF was the fifth most common non-methadone synthetic opioid detected and a quantitative method was developed to better understand the significance of this compound. A full quantitative validation was performed utilizing liquid chromatography–tandem mass spectrometry (LC–MS/MS). All cases submitted between May 2017 and December 2018 that tested positive for FIBF qualitatively were chosen for quantitation. In addition to compiling FIBF concentrations, user demographics and concurrent drug use were also investigated. There were 247 FIBF-positive cases that were tested with blood concentrations ranging from < 0.1 to 331 ng/mL. The most commonly detected drugs in conjunction with FIBF were other opioids, benzodiazepines, cocaine, cannabinoids and ethanol. The most frequent users were male, White, and between 35 and 54 years of age. The concentrations of FIBF varied widely and showed no clear distinction when considering various case types. Although most often used in tandem with other drugs of abuse, the danger of this compound was demonstrated by the fact that FIBF was also reported as the sole intoxicant responsible for death. The development of a quantitative method for FIBF has been beneficial at the OCME due to the significant number of positive cases reported and the current lack of sufficient published information on this analog. To our knowledge, there are only two papers that include FIBF concentrations in four cases; this article gives the largest number (247 cases) of FIBF levels in blood samples of its users to aid in the interpretation and analysis of significance of this compound.

Validation of an LC-MS/MS Method for the Quantification of 13 Designer Benzodiazepines in Blood

The misuse of designer benzodiazepines, as an alternative to prescription benzodiazepines and for drug-facilitated sexual assaults, has emerged as a growing threat, due in part to the ease of purchasing these drugs on the internet at low prices. Causing concern for safety is the lack of dosage information resulting in users self-medicating, often leading to unintended overdoses, coma or death at higher doses. With limited published data regarding the quantification of designer benzodiazepines in forensic cases, a method was validated for the determination of 13 designer benzodiazepines in postmortem blood, to add to the in-house method that already included a limited number of common designer benzodiazepines. The developed method included 3-hydroxyphenazepam, clobazam, clonazolam, delorazepam, deschloroetizolam, diclazepam, flualprazolam, flubromazepam, flubromazolam, flunitrazolam, meclonazepam, nifoxipam and pyrazolam in 0.5mL postmortem blood using liquid chromatography-tandem mass spectrometry. The analytes were treated with solid phase extraction before undergoing separation on a C18 column and analyzed on the mass spectrometer in electrospray positive mode using multiple reaction monitoring. The linear range of the calibration curve was 1-200ng/mL and up to 500ng/mL for 3-hydroxyphenazepam, clobazam, flubromazepam and pyrazolam. The limits of detection and quantitation were 0.5ng/mL (signal-to-noise ratio >3) and 1ng/mL, respectively. The calculated bias, intra-day imprecision, relative standard deviation (RSD) and inter-day imprecision RSD were ±12%, 3-20% and 4-21%. Matrix effects ranged from -52% to 33% with RSD values ranging from 3-20%, indicating consistent effects throughout multiple sources. Recovery ranged from 35 to 90%, where only two compounds were <50%. Other parameters tested included carryover, stability, interference and dilution integrity, which all yielded acceptable results. With the application of this method to blood specimens from the New York City Office of Chief Medical Examiner, this validated method proved to be simple, reproducible, sensitive and robust.

Lessons learned from testing cardiac channelopathy and cardiomyopathy genes in individuals who died suddenly: A two-year prospective study in a large medical examiner's office with an in-house molecular genetics laboratory and genetic counseling services.

This is a comprehensive review and analysis of 254 cases tested consecutively in the in-house College of American Pathologist-accredited molecular genetics laboratory within the New York City Office of Chief Medical Examiner between October 2015 and February 2018, using a multigene cardiac panel composed of 95 genes associated with cardiac channelopathy and cardiomyopathy. Demographics, autopsy findings, medical history, and postmortem genetic testing results were collected for each case. The majority of decedents were adults (>25years old, 52.7%), followed by infants (<12months, 25.6%), young adults (19-25years old, 11.4%), and children (1-18years old, 10.2%). There were more males (64.2%) than females (35.8%). The racial/ethnic composition of decedents was 40.2% Black, 29.9% Hispanic, 22.4% White, 5.1% Asian/Pacific Islander, and 2.8% mixed/unspecified. Overall, 45.7% of decedents had a negative autopsy, and the remaining had one to four cardiac findings (cardiac hypertrophy, dilation, atherosclerosis, and fatty change). Twenty-seven pathogenic/likely pathogenic variants (P/LP) and 99 variants of uncertain significance (VUS) were identified in 10.6% and 39% of decedents respectively. P/LP and VUS were found in 51 cardiac genes of the total 95 genes, where MYBPC3, TTN (predicted truncating variants), KCNH2, RYR2 and DSP genes had more than two P/LP variants identified. Among the 73 decedents who were suspected of having cardiac arrhythmia or cardiomyopathy, 20.3% had P/LP variants and 47.9% had VUS; among 23 decedents who had hypertensive cardiovascular diseases and 20 decedents with a history of substance use, 13% and 30% had P/LP variants, respectively. There were 26 referrals from medical examiners for genetic counseling and the outcomes are discussed. The study demonstrates characteristics of the diverse population typically seen by medical examiners in an urban center and our results support a broader implementation of molecular testing in sudden death.

Functional characterization of SCN10A variants in several cases of sudden unexplained death

BackgroundMultiple genome-wide association studies (GWAS) and targeted gene sequencing have identified common variants in SCN10A in cases of PR and QRS duration abnormalities, atrial fibrillation and Brugada syndrome. The New York City Office of Chief Medical Examiner has now also identified five SCN10A variants of uncertain significance in six separate cases within a cohort of 330 sudden unexplained death events. The gene product of SCN10A is the Nav1.8 sodium channel. The purpose of this study was to characterize effects of these variants on Nav1.8 channel function to provide better information for the reclassification of these variants. Methods and resultsPatch clamp studies were performed to assess effects of the variants on whole-cell Nav1.8 currents. We also performed RNA-seq analysis and immunofluorescence confocal microcopy to determine Nav1.8 expression in heart. We show that four of the five rare ‘variants of unknown significance’ (L388M, L867F, P1102S and V1518I) are associated with altered functional phenotypes. The R756W variant behaved similar to wild-type under our experimental conditions. We failed to detect Nav1.8 protein expression in immunofluorescence microscopy in rat heart. Furthermore, RNA-seq analysis failed to detect full-length SCN10A mRNA transcripts in human ventricle or mouse specialized cardiac conduction system, suggesting that the effect of Nav1.8 on cardiac function is likely to be extra-cardiac in origin. ConclusionsWe have demonstrated that four of five SCN10A variants of uncertain significance, identified in unexplained death, have deleterious effects on channel function. These data extend the genetic testing of SUD cases, but significantly more clinical evidence is needed to satisfy the criteria needed to associate these variants with the onset of SUD.