Sudden Death in Pediatric Patient With Dilated Cardiomyopathy Due to Founder Variant in : Case Report.

The gene encodes a transcription factor that plays a role in atrioventricular nodal and myocardial development. Pathogenic variants of are associated with congenital heart disease and sudden cardiac death. The missense variant in this case is one of the more common ones in Northern Europe and has high penetrance in familial cases.

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

Background: Sudden 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.

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.

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

Background: Multiple 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.

Functional characterization of ABCC9 variants identified in sudden unexpected natural death.

Background: Genetic variation in ion channel genes ('channelopathies') are often associated with inherited arrhythmias and sudden death. Genetic testing ('molecular autopsies') of channelopathy genes can be used to assist in determining the likely causes of sudden unexpected death. However, different in silico approaches can yield conflicting pathogenicity predictions and assessing their impact on ion channel function can assist in this regard.

Molecular autopsy: using the discovery of a novel de novo pathogenic variant in the KCNH2 gene to inform healthcare of surviving family.

Background: Molecular testing of the deceased (Molecular Autopsy) is an overlooked area in the United States healthcare system and is not covered by medical insurance, leading to ineffective care for surviving families of thousands of sudden unexpected natural deaths each year. We demonstrated the precision management of surviving family members through the discovery of a novel pathogenic variant in a decedent.

Methods: Forensic investigation and molecular autopsy were performed on an 18-year-old female who died suddenly and unexpectedly.

Functional reclassification of variants of uncertain significance in the HCN4 gene identified in sudden unexpected death.

The HCN4 gene encodes a subunit of the hyperpolarization-activated cyclic nucleotide-gated channel, type 4 that is essential for the proper generation of pacemaker potentials in the sinoatrial node. The HCN4 gene is often present in targeted genetic testing panels for various cardiac conduction system disorders and there are several reports of HCN4 variants associated with conduction disorders. Here, we report the in vitro functional characterization of four rare variants of uncertain significance (VUS) in HCN4, identified through testing a cohort of 296 sudden unexpected natural deaths.

Genetic testing in sudden unexpected natural death in the young: New York City Office of Chief Medical Examiner's experience and perspective.

Postmortem genetic testing is a diagnostic tool that is becoming increasingly utilized. The benefits and limitations of genetic testing in cases of sudden, unexpected death in the young (≤ 40 years old) are reviewed from the perspective of the Office of Chief Medical Examiner of the City of New York, whose Molecular Genetics Laboratory, accredited by College of American Pathologists, has had 15 years of postmortem testing experience. Challenges to the interpretation and communication of testing results are highlighted, and opportunities for improving testing yield are discussed for age groups across the lifespan, from infancy to adulthood.

Functional characterization of TRPM4 variants identified in sudden unexpected natural death.

Background: The TRPM4 gene encodes the subunit of the Ca-activated nonselective cation channel, which is enriched in the specialized cardiac conduction system and Purkinje fibers. To date, several putative disease-causing variants in TRPM4 have been reported to be associated with cardiac arrhythmia and progressive conduction disease. Here, we report the functional effects of previously uncharacterized variants of uncertain significance (VUS) that we have found while performing a "genetic autopsy" in individuals who have suffered sudden unexpected death (SUD) in the New York City area.

Phenotypic variations in carriers of predicted protein-truncating genetic variants in MYBPC3: an autopsy-based case series.

Our aim is to characterize predicted protein-truncating variants (PTVs) in MYBPC3, the gene most commonly associated with hypertrophic cardiomyopathy (HCM), found in a series of autopsied HCM cases after sudden unexpected cardiac death. All cases underwent death scene investigation, gross and microscopic autopsies, toxicological testing, a review of medical records, and a molecular analysis of 95 cardiac genes. We found four pathogenic PTVs in MYBPC3 among male decedents.

Report and Recommendations of the Association of Pathology Chairs' Autopsy Working Group.

Autopsy has been a foundation of pathology training for many years, but hospital autopsy rates are notoriously low. At the 2014 meeting of the Association of Pathology Chairs, some pathologists suggested removing autopsy from the training curriculum of pathology residents to provide additional months for training in newer disciplines, such as molecular genetics and informatics. At the same time, the American Board of Pathology received complaints that newly hired pathologists recently certified in anatomic pathology are unable to perform an autopsy when called upon to do so.

Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths.

Background: Genetic variant interpretation contributes to testing yield differences reported for sudden unexplained death. Adapting a high-resolution variant interpretation framework, which considers disease prevalence, reduced penetrance, genetic heterogeneity, and allelic contribution to determine the maximum tolerated allele count in gnomAD, we report an evaluation of cardiac channelopathy and cardiomyopathy genes in a large, demographically diverse sudden unexplained death cohort that underwent thorough investigation in the United States' largest medical examiner's office.

Methods And Results: The cohort has 296 decedents: 147 Blacks, 64 Hispanics, 49 Whites, 22 Asians, and 14 mixed ethnicities; 142 infants (1 to 11 months), 39 children (1 to 17 years), 74 young adults (18 to 34 years), and 41 adults (35 to 55 years).

Whole Exome Sequencing Reveals Severe Thrombophilia in Acute Unprovoked Idiopathic Fatal Pulmonary Embolism.

Background: Acute unprovoked idiopathic fatal pulmonary embolism (IFPE) causes sudden death without an identifiable thrombogenic risk. We aimed to investigate the underlying genomic risks of IFPE through whole exome sequencing (WES).

Methods: We reviewed 14years of consecutive out-of-hospital fatal pulmonary embolism records (n=1478) from the ethnically diverse population of New York City.

Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths.

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.

Molecular diagnostics of cardiovascular diseases in sudden unexplained death.

The most challenging type of sudden cardiac death is sudden unexplained death. The etiologies for sudden unexplained death are diverse and not necessarily confined to the cardiovascular system. Nevertheless, certain cardiovascular diseases, particularly cardiac channelopathies and cardiomyopathies, are known to play significant roles in sudden deaths.

Examination of the Cardiac Explant.

Examination of cardiac explants is a challenge to the surgical pathologist. This is due to the complex anatomy of the heart, the numerous pathologies unique to the heart, and the complexities of cardiovascular interventions including the transplant procedure itself. The dissection technique described permits complete evaluation of the heart with good photographic and histologic documentation while maintaining the integrity of the specimen.

Women have less severe and extensive coronary atherosclerosis in fatal cases of ischemic heart disease: an autopsy study.

Objective: The study aims to evaluate sex differences in extent and severity of coronary artery disease (CAD) and myocardial findings at autopsy among young people with fatal ischemic heart disease (IHD).

Background: Women with acute coronary syndrome are less likely than men to display obstructive CAD at angiography. This suggests unique mechanisms of acute coronary syndrome exist in women or may reflect prehospital death of women with the most severe CAD.

Mortality in cerebral palsy (CP): the importance of the cause of CP on the manner of death.

Cerebral palsy (CP) is a nonprogressive motor deficit present or sustained in the perinatal period. We reviewed the files of the Office of Chief Medical Examiner of the City of New York for the 1997-2001 interval seeking those with any mention of cerebral palsy. There were 26 such cases, including 18 natural deaths, three accidents, two homicides, two therapeutic complications, and one death classified as undetermined.

Spontaneous cerebellar hemorrhage in children.

Spontaneous cerebellar hemorrhages are a rare but often fatal occurrence in children. Although there are several predisposing factors such as blood dyscrasias or astrocytomas, the most common cause of cerebellar hemorrhage in an otherwise healthy child is the rupture of a vascular malformation. We reviewed the files of the Office of Chief Medical Examiner of the City of New York and found four such instances over a period of less than two years.

Schizophrenia as a cause of death.

Schizophrenia is a chronic disorder that is associated with increased mortality. Although traumatic deaths account for most of this increase, there is also an increased rate of natural deaths in this population. Altered autonomic physiology in this group might contribute to death.