Autopsy-negative Sudden Unexplained Death Research Articles

Sudden Cardiac Death in National Collegiate Athletic Association Athletes: A 20-Year Study.

Understanding the incidence, causes, and trends of sudden cardiac death (SCD) among young competitive athletes is critical to inform preventive policies. This study included National Collegiate Athletic Association athlete deaths during a 20-year time frame (July 1, 2002, through June 30, 2022). Athlete deaths were identified through 4 separate independent databases and search strategies (National Collegiate Athletic Association resolutions list, Parent Heart Watch database and media reports, National Center for Catastrophic Sports Injury Research database, and insurance claims). Autopsy reports and medical history were reviewed by an expert panel to adjudicate causes of SCD. A total of 143 SCD cases in National Collegiate Athletic Association athletes were identified from 1102 total deaths. The National Collegiate Athletic Association resolutions list identified 117 of 143 (82%), the Parent Heart Watch database or media reports identified 89 of 143 (62%), the National Center for Catastrophic Sports Injury Research database identified 63 of 143 (44%), and insurance claims identified 27 of 143 (19%) SCD cases. The overall incidence of SCD was 1:63 682 athlete-years (95% CI, 1:54 065-1:75 010). Incidence was higher in male athletes than in female athletes (1:43 348 [95% CI, 1:36 228-1:51 867] versus 1:164 504 [95% CI, 1:110 552-1:244 787] athlete-years, respectively) and Black athletes compared with White athletes (1:26 704 [1:20 417-1:34 925] versus 1:74 581 [1:60 247-1:92 326] athlete-years, respectively). The highest incidence of SCD was among Division I male basketball players (1:8188 [White, 1:5848; Black, 1:7696 athlete-years]). The incidence rate for SCD decreased over the study period (5-year incidence rate ratio, 0.71 [95% CI, 0.61-0.82]), whereas the rate of noncardiovascular deaths remained stable (5-year incidence rate ratio, 0.98 [95% CI, 0.94-1.04]). Autopsy-negative sudden unexplained death (19.5%) was the most common postmortem examination finding, followed by idiopathic left ventricular hypertrophy or possible cardiomyopathy (16.9%) and hypertrophic cardiomyopathy (12.7%), in cases with enough information for adjudication (118 of 143). Eight cases of death were attributable to myocarditis over the study period (1 case from January 1, 2020, through June 30, 2022), with none attributed to COVID-19 infection. SCD events were exertional in 50% of cases. Exertional SCD was more common among those with coronary artery anomalies (100%) and arrhythmogenic cardiomyopathy (83%). The incidence of SCD in college athletes has decreased. Male sex, Black race, and basketball are associated with a higher incidence of SCD.

Abstract 13427: Incidence and Causes of Sudden Cardiac Death in National Collegiate Athletic Association Athletes: A 20-year Study

Background: The incidence and causes of sudden cardiac death (SCD) among young competitive athletes impact prevention strategies yet remain incompletely understood. Methods: National Collegiate Athletic Association (NCAA) athlete deaths from 7/1/2002-6/30/2022 were identified through 4 independent databases/search strategies. Autopsy reports and medical history were reviewed by an expert panel to adjudicate causes of SCD. Poisson regression was used to calculate incidence rate ratios (IRR) for 5-year intervals over the 20-year study. Results: A total of 143 SCD cases were identified among 1102 athlete deaths and 9,106,516 athlete-years (AYs). The incidence of SCD among NCAA athletes was 1:63,682 AYs [95% CI 1:54,065, 1:75,010]. Incidence was higher in males compared to females (1:43,348 vs. 1:164,504 AYs) and Black compared to White athletes (1:27,217 vs. 1:74,581 AYs). The highest incidence of SCD was among Division 1 male basketball players (1:8,188; White 1:5,848; Black 1:7,696 AYs). The incidence rate for SCD decreased over the study period (5-year IRR 0.71 [95% CI 0.61,0.82]), whereas the rate of non-cardiovascular deaths remained stable (5-year IRR 0.98 [95% CI 0.94,1.04]; Figure 1A ). Autopsy-negative sudden unexplained death (AN-SUD, 19.5%) was the most common post-mortem exam finding, followed by idiopathic left ventricular hypertrophy/possible cardiomyopathy (CM, 16.9%) and hypertrophic CM (12.7%) in cases with enough information for adjudication (118/143, Figure 1B ). There were 8 cases of myocarditis, with none attributed to COVID-19 infection. SCD events occurred most commonly during exertion among athletes with coronary artery anomalies (100%) and arrhythmogenic CM (83%), whereas AN-SUD and hypertrophic CM had a higher proportion of non-exertional SCD (44% and 40%, respectively). Conclusions: The incidence of SCD in college athletes has decreased. Male sex, Black race, and basketball are associated with a higher incidence of SCD.

Sudden cardiac death in sports

Problem and objective: To inform about the incidence, causes and prevention measures of sudden cardiac death in sports. Methods: A literature search was performed (PubMed, Web of Science, Researchgate) using the terms sudden cardiac death (SCD), sudden cardiac arrest (SCA), sudden death, cardiopulmonary resuscitation, sport, exercise and athlete. Observational studies, systematic reviews and meta-analyses that examined SCD/SCA during exercise or up to one hour afterwards in recreational, competitive or elite athletes were considered. Results: Of 6350 study titles and abstracts 11 full-text studies were included in this clinical review. When the incidence was calculated based on multiple sports, it varied between populations and ranged from 0.1 to 2.9/100,000 athlete-years (AY). The incidence was highest in male professional basketball players, with 19/100,000 AY. The most frequent cause of SCD/SCA in athletes >35 years was coronary artery disease (CAD), while in younger athletes the predominating underlying pathologies (autopsy-negative sudden unexplained death, myocarditis, cardiomyopathies, coronary artery anomalies and premature CAD) differed by region. The most effective screening tool for cardiovascular disease in athletes is the ECG. Survival after CPR is substantially influenced by the use of an automated external defibrillator (AED). Discussion: SCD/SCA in athletes is a rare but very tragic event. Incidence rates in athletes differ among populations, studies, and sports. Some degree of underreporting can be assumed as there is no mandatory reporting of sports-related SCD/SCA in most countries and few scientific registries exist. Potentially, primary screening measures could be adapted to the regionally different causes of SCD/SCA. In addition, training athletes and staff in the use of an AED is paramount to improving survival rates.

PO-615-05 ACACETIN, A POTENT TRANSIENT OUTWARD CURRENT BLOCKER, MAY BE A NOVEL THERAPEUTIC FOR KCND3-ENCODED KV4.3 GAIN-OF-FUNCTION-ASSOCIATED J-WAVE SYNDROMES

The transient outward current (Ito) that mediates early (phase 1) repolarization is conducted by the KCND3-encoded Kv4.3 pore-forming α-subunit. KCND3 gain-of-function mutations have been reported previously as a pathogenic substrate for J wave syndromes (JWS), including the Brugada syndrome (BrS) and early repolarization syndrome (ERS), as well as autopsy-negative sudden unexplained death (SUD). Acacetin, a natural flavone, is a potent Ito current blocker. We hypothesize that Acacetin may be a novel therapeutic for KCND3-mediated JWS. KCND3-V392I was identified in an 18-year-old male with JWS/ERS, and a history of cardiac arrest including ventricular tachycardia/fibrillation and atrial fibrillation/flutter. KCND3-V392I was engineered by site directed mutagenesis and expressed in TSA201 cells. Gene-edited/variant-corrected isogenic control and patient-specific pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from the KCND3-V392I-positive patient were generated. Ito currents and action potentials (APs) were recorded before and after treatment with Acacetin using the whole cell patch-clamp and multielectrode array (MEA) technique. Western blot and immunocytochemistry were performed to investigate KCND3 expression. KCND3-V392I demonstrated a marked gain-of-function phenotype, increasing peak Ito current density by 92% (p<0.05 vs. KCND3-WT) in TSA201 cells and by 61% in Kv4.3-V392I iPSC-CM (p<0.05 vs. isogenic control). KCND3 transcript and translate expression was increased significantly in KCND3-V392I-derived iPSC-CMs (p<0.05 vs. isogenic control). While KCND3-WT revealed an IC50 of 7.2±1.0 μM for Acacetin effect, 30 μM Acacetin dramatically inhibited KCND3-V392I peak Ito current density by 96% (p<0.05 vs. before Acacetin). 10 μM Acacetin, a concentration approaching its IC50 value, inhibited Ito by 54% (P<0.05 vs. before Acacetin) in patient-derived iPSC-CMs and reduced the accentuated AP notch displayed in KCND3-V392I-derived iPSC-CMs. This pre-clinical study provides pharmacological and functional evidence to suggest that Acacetin may be a novel therapeutic for patients with KCND3 gain-of-function-associated JWS by inhibiting Ito and abolishing the accentuated AP notch in patient-derived iPSC-CMs.

Aetiology and incidence of sudden cardiac arrest and death in young competitive athletes in the USA: a 4-year prospective study

ObjectiveTo investigate the aetiology and incidence of sudden cardiac arrest and death (SCA/D) in US competitive athletes.MethodsProspective surveillance was conducted from 1 July 2014 to 30 June 2018 through the...

Etiology of Sudden Cardiac Arrest and Death in US Competitive Athletes: A 2-Year Prospective Surveillance Study.

To determine the etiology of sudden cardiac arrest and death (SCA/D) in competitive athletes through a prospective national surveillance program. Sudden cardiac arrest and death cases in middle school, high school, college, and professional athletes were identified from July 2014 to June 2016 through traditional and social media searches, reporting to the National Center for Catastrophic Sports Injury Research, communication with state and national high school associations, review of the Parent Heart Watch database, and search of student-athlete deaths on the NCAA Resolutions List. Autopsy reports and medical records were reviewed by a multidisciplinary panel to determine the underlying cause. US competitive athletes with SCA/D. Etiology of SCA/D. A total of 179 cases of SCA/D were identified (74 arrests with survival, 105 deaths): average age 16.6 years (range 11-29), 149 (83.2%) men, 94 (52.5%) whites, and 54 (30.2%) African American. One hundred seventeen (65.4%) had an adjudicated diagnosis, including 83 deaths and 34 survivors. The most common etiologies included hypertrophic cardiomyopathy (19, 16.2%), coronary artery anomalies (16, 13.7%), idiopathic left ventricular hypertrophy/possible cardiomyopathy (13, 11.1%), autopsy-negative sudden unexplained death (8, 6.8%), Wolff-Parkinson-White (8, 6.8%), and long QT syndrome (7, 6.0%). Hypertrophic cardiomyopathy was more common in male basketball (23.3%), football (25%), and African American athletes (30.3%). An estimated 56.4% of cases would likely demonstrate abnormalities on an electrocardiogram. The etiology of SCA/D in competitive athletes involves a wide range of clinical disorders. More robust reporting mechanisms, standardized autopsy protocols, and accurate etiology data are needed to better inform prevention strategies.

Plakophilin-2 Truncation Variants in Patients Clinically Diagnosed With Catecholaminergic Polymorphic Ventricular Tachycardia and Decedents With Exercise-Associated Autopsy Negative Sudden Unexplained Death inthe Young.

This study determined if radical plakophilin-2 (PKP2) variants might underlie some cases of clinically diagnosed catecholaminergic polymorphic ventricular tachycardia (CPVT) and exercise-associated, autopsy-negative sudden unexplained death in the young (SUDY). Pathogenic variants in PKP2 cause arrhythmogenic right ventricular cardiomyopathy (ARVC). Recently, a cardiomyocyte-specific PKP2 knockout mouse model revealed that loss of PKP2 markedly reduced expression of genescritical in intracellular calcium handling. The mice with structurally normal hearts exhibited isoproterenol-triggered polymorphic ventricular arrhythmias that mimicked CPVT. A PKP2 gene mutational analysis was performed on DNA from 18 unrelated patients (9 males; average age at diagnosis: 19.6 ± 12.8 years) clinically diagnosed with CPVT but who were RYR2-, CASQ2-, KCNJ2-, and TRDN-negative, and 19 decedents with SUDY during exercise (13 males; average age at death: 14 ± 3 years). Only radical (i.e., frame-shift, canonical splice site, or nonsense) variants with a minor allele frequency of≤0.00005 in the genome aggregation database (gnomAD) were considered pathogenic. Radical PKP2 variants were identified in 5 of 18 (27.7%) CPVT patients and 1 of 19 (5.3%) exercise-related SUDY cases compared with 96 of 138,632 (0.069%) individuals in gnomAD (p= 3.1× 10-13). Cardiac imaging or autopsy demonstrated a structurally normal heart in all patients at the time of their CPVT diagnosis or sudden death. Our data suggested that the progression of the PKP2-dependent electropathy can be independent of structural perturbations and can precipitate exercise-associated sudden cardiac arrest or sudden cardiac death before thepresence of overt cardiomyopathy, which clinically mimics CPVT, similar to the PKP2 knockout mouse model. Thus,CPVT and SUDY genetic test panels should now include PKP2.

Exome analysis in 34 sudden unexplained death (SUD) victims mainly identified variants in channelopathy-associated genes.

Sudden cardiac death (SCD) is one of the major causes of mortality worldwide, mostly involving coronary artery disease in the elderly. In contrary, sudden death events in young victims often represent the first manifestation of undetected genetic cardiac diseases, which remained without any symptoms during lifetime. Approximately 30% of these sudden death cases have no definite cardiac etiology after a comprehensive medicolegal investigation and are therefore termed as sudden unexplained death (SUD) cases. Advances in high-throughput sequencing approaches have provided an efficient diagnostic tool to identify likely pathogenic variants in cardiovascular disease-associated genes in otherwise autopsy-negative SUD cases. The aim of this study was to genetically investigate a cohort of 34 unexplained death cases by focusing on candidate genes associated with cardiomyopathies and channelopathies. Exome analysis identified potentially disease-causing sequence alterations in 29.4% of the 34 SUD cases. Six (17.6%) individuals had variants with likely functional effects in the channelopathy-associated genes AKAP9, KCNE5, RYR2, and SEMA3A. Interestingly, four of these six SUD individuals were younger than 18years of age. Since the total SUD cohort of this study included five children and adolescents, post-mortem molecular autopsy screening indicates a high diagnostic yield within this age group. Molecular genetic testing represents a valuable approach to uncover the cause of death in some of the SUD victims; however, 70-80% of the cases still remain elusive, emphasizing the importance of additional research to better understand the pathological mechanisms leading to a sudden death event.

Sudden unexplained cardiac deaths in young adults: a call for multidisciplinary approach

The investigation of death in young (<35 years), previously fit individuals, calls for a detailed autopsy with emphasis placed upon the examination of the heart. In most instances, the cause of cardiac death can be identified during autopsy. However, a large percentage of sudden deaths remain unexplained even after comprehensive medicolegal investigation, including autopsy, and are labelled as autopsy-negative sudden unexplained cardiac death (SUD). Still, when you look to the law, an autopsy, a much needed truth-finding-instrument, usually is not mandatory and is left up to the discretion of various medical or legal authorities, which when making a decision, balance various, often conflicting interests of the state and society on the one hand and of the deceased and his family on the other. Cardiac molecular autopsy calls for a close cooperation between medical examiner, pathologist, family physician, cardiologist, geneticist, and the relatives. Multidisciplinary approach and the identification of genetic cause of SUD enable proper genetic counselling for surviving relatives as well as for implementing specific preventive/therapeutic strategies, e.g. implantable cardioverter-defibrillator (ICD) implantation.

Incidence and Etiology of Sudden Cardiac Death: New Updates for Athletic Departments.

Context:Sudden cardiac death (SCD) in a young athlete is a tragic event and is the leading medical cause of death in this population. The precise incidence of SCD in young athletes has been subject of debate, with studies reporting drastically different rates (1:917,000 athlete-years (AYs) to 1:3000 AYs) depending on the methodological design of the investigation or the targeted population.Evidence Acquisition:A literature search was performed in PubMed using the terms: incidence, sudden cardiac death, sudden death, sudden cardiac arrest, etiology, pathology, registry, athlete, young, children, and adolescents. Articles were reviewed for relevance and included if they contained information on the incidence of SCD in athletes or young persons up to the age of 35 years.Study Design:Clinical review.Level of Evidence:Level 5.Results:Studies of high quality and rigor consistently yield an incidence of 1:50,000 AYs in college athletes and between 1:50,000 and 1:80,000 AYs for high school athletes, with certain subgroups that appear to be at particularly high risk, including the following: men, basketball players, and African Americans. Initial reports suggest that the most common cause of SCD is hypertrophic cardiomyopathy (HCM). However, more comprehensive investigations in the United States and international populations—athletes, nonathletes, and military—support that the most common finding on autopsy in young individuals with SCD is actually a structurally normal heart (autopsy-negative sudden unexplained death).Conclusion:SCD is the leading cause of death in athletes during exercise and usually results from intrinsic cardiac conditions that are triggered by the physiologic demands of vigorous exercise. Current rates of SCD appear to be at least 4 to 5 times higher than previously estimated, with men, African Americans, and male basketball players being at greatest risk. Emerging data suggest that the leading finding associated with SCD in athletes is actually a structurally normal heart (autopsy-negative sudden unexplained death).

Incidence and Etiology of Sudden Cardiac Arrest and Death in High School Athletes in the United States

ObjectiveTo determine the incidence and etiology of sudden cardiac arrest and death (SCA/D) in US high school athletes. Patients and MethodsA prospective media database of SCA/D was queried for cases aged 14 to 18 years from 7 states over 6 school years (September 1, 2007, to August 30, 2013). Event details were investigated to determine participation on a high school athletic team, sex, sport, and occurrence during school-sponsored activity or exertion. National sports participation numbers were used and a conversion factor was applied to account for multisport athletes. Autopsy reports were reviewed and cause of death was adjudicated by an expert panel. ResultsA total of 16,390,409 million athlete-seasons representing 6,974,640 athlete-years (AY) were examined, encompassing 36% of the total US high school athlete population. A total of 104 cases of SCA/D were identified (35 SCA with survival and 69 sudden cardiac deaths [SCDs]). The rate of SCD was 1:101,082 AY and of SCA/D 1:67,064 AY. Eighty-eight percent (92) of events occurred in male athletes. The rate of SCA/D in male athletes was 1:44,832 AY and in female athletes 1:237,510 AY (incidence rate ratio, 5.3; 95% CI, 2.9-10.6; P<.001). Men's basketball was the highest risk sport with an SCA/D incidence of 1:37,087 AY followed by men's football at 1:86,494 AY. Men's basketball and football athletes accounted for 57% (39) of deaths. Eighty percent of SCDs (55 of 69) were exertional and 55% (38 of 69) occurred while playing for a school-sponsored team. Autopsy reports were obtained in 73% (50) of cases. The most common findings of autopsy were idiopathic left ventricular hypertrophy or possible cardiomyopathy (13 of 50 [26%]), autopsy-negative sudden unexplained death (9 of 50 [18%]), hypertrophic cardiomyopathy (7 of 50 [14%]), and myocarditis (7 of 50 [14%]). ConclusionThe rate of SCA/D in male high school athletes was 1:44,832 AY, with almost half due to possible or confirmed cardiomyopathy disease. It is likely that many cases were not identified because of reliance on media reports, and these numbers represent a minimum estimate.

Molecular and Functional Characterization of Rare CACNA1C Variants in Sudden Unexplained Death in the Young.

Perturbations in the CACNA1C-encoded L-type calcium channel α-subunit have been linked recently to heritable arrhythmia syndromes, including Timothy syndrome, Brugada syndrome, early repolarization syndrome, and long QT syndrome. These heritable arrhythmia syndromes may serve as a pathogenic basis for autopsy-negative sudden unexplained death in the young (SUDY). However, the contribution of CACNA1C mutations to SUDY is unknown. We set out to determine the spectrum, prevalence, and pathophysiology of rare CACNA1C variants in SUDY. Mutational analysis of CACNA1C was conducted in 82 SUDY cases using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct sequencing. Identified variants were engineered using site-directed mutagenesis, and heterologously expressed in TSA-201 or HEK293 cells. Two SUDY cases (2.4%) harbored functional variants in CACNA1C. The E850del and N2091S variants involve highly conserved residues and localize to the II-III linker and C-terminus, respectively. Although observed in publically available exome databases, both variants confer abnormal CaV 1.2 electrophysiological characteristics. Examination of the electrophysiological properties revealed the E850del mutation in CACNA1C led to a 95% loss-of-function in ICa , and the N2091S variant led to a 105% gain-of-function in ICa. Additionally, N2091S led to minor kinetic alterations including a -3.4 mV shift in V1/2 of activation. This study provides molecular and functional evidence that rare CACNA1C genetic variants may contribute to the underlying pathogenic basis for some cases of SUDY in either a gain or loss-of-function mechanism.

Whole-Exome Molecular Autopsy After Exertion-Related Sudden Unexplained Death in the Young.

Targeted postmortem genetic testing of the 4 major channelopathy-susceptibility genes (KCNQ1, KCNH2, SCN5A, and RYR2) have yielded putative pathogenic mutations in ≤30% of autopsy-negative sudden unexplained death in the young (SUDY) cases with highest yields derived from the subset of exertion-related SUDY. Here, we evaluate the role of whole-exome sequencing in exertion-related SUDY cases. From 1998 to 2010, 32 cases of exertion-related SUDY were referred by Medical Examiners for a cardiac channel molecular autopsy. A mutational analysis of the major long-QT syndrome-susceptibility genes (KCNQ1, KCNH2, and SCN5A) and catecholaminergic polymorphic ventricular tachycardia-susceptibility gene (RYR2) identified a putative pathogenic mutation in 11 cases. Whole-exome sequencing was performed on the remaining 21 targeted gene-negative SUDY cases. After whole-exome sequencing, a gene-specific surveillance of all genes (N=100) implicated in sudden death was performed to identify putative pathogenic mutation(s). Three of these 21 decedents had a clinically actionable, pathogenic mutation (CALM2-F90L, CALM2-N98S, and PKP2-N634fs). Of the 18 remaining cases, 7 hosted at least 1 variant of unknown significance with a minor allele frequency <1:20 000. The overall yield of pathogenic mutations was higher among decedents aged 1 to 10 years (10/11, 91%) than those aged 11 to 19 years (4/21, 19%, P=0.0001). Molecular screening in this clinical scenario is appropriate with a pathogenic mutation detection rate of 44% using direct DNA sequencing followed by whole-exome sequencing. Only 5 of the 100 interrogated sudden death genes hosted actionable pathogenic mutations for more than one third of these exertion-related, autopsy-negative SUDY cases.

Erratum to: Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases.

Sudden death of healthy young adults in the absence of any medical reason is generally categorised as autopsy-negative sudden unexplained death (SUD). Approximately 30 % of all SUD cases can be explained by lethal sequence variants in cardiac genes causing disturbed ion channel functions (channelopathies) or minimal structural heart abnormalities (cardiomyopathies). The aim of this study was to perform whole-exome sequencing (WES) in five young SUD cases in order to identify potentially disease-causing mutations with a focus on 184 genes associated with cardiac diseases or sudden death. WES analysis enabled the identification of damaging-predicted cardiac sequence alterations in three out of five SUD cases. Two SUD victims carried disease-causing variants in long QT syndrome (LQTS)-associated genes (KCNH2, SCN5A). In a third case, WES identified variants in two genes involved in mitral valve prolapse and thoracic aortic aneurism (DCHS1, TGFβ2). The genome of a fourth case carried several minor variants involved in arrhythmia pointing to a multigene influence that might have contributed to sudden death. Our results confirm that post-mortem genetic testing in SUD cases in addition to the conventional autopsy can help to identify familial cardiac diseases and can contribute to the identification of genetic risk factors for sudden death.

Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases.

Sudden death of healthy young adults in the absence of any medical reason is generally categorised as autopsy-negative sudden unexplained death (SUD). Approximately 30% of all SUD cases can be explained by lethal sequence variants in cardiac genes causing disturbed ion channel functions (channelopathies) or minimal structural heart abnormalities (cardiomyopathies). The aim of this study was to perform whole-exome sequencing (WES) in five young SUD cases in order to identify potentially disease-causing mutations with a focus on 184 genes associated with cardiac diseases or sudden death. WES analysis enabled the identification of damaging-predicted cardiac sequence alterations in three out of five SUD cases. Two SUD victims carried disease-causing variants in long QT syndrome (LQTS)-associated genes (KCNH2, SCN5A). In a third case, WES identified variants in two genes involved in mitral valve prolapse and thoracic aortic aneurism (DCHS1, TGFβ2). The genome of a fourth case carried several minor variants involved in arrhythmia pointing to a multigene influence that might have contributed to sudden death. Our results confirm that post-mortem genetic testing in SUD cases in addition to the conventional autopsy can help to identify familial cardiac diseases and can contribute to the identification of genetic risk factors for sudden death.

Genetic screening in sudden cardiac death in the young can save future lives.

BackgroundAutopsy of sudden cardiac death (SCD) in the young shows a structurally and histologically normal heart in about one third of cases. Sudden death in these cases is believed to be attributed in a high percentage to inherited arrhythmogenic diseases. The purpose of this study was to investigate the value of performing post-mortem genetic analysis for autopsy-negative sudden unexplained death (SUD) in 1 to 35 year olds.Methods and resultsFrom January 2009 to December 2011, samples from 15 cases suffering SUD were referred to the Department of Clinical Genetics, Umeå University Hospital, Sweden, for molecular genetic evaluation. PCR and bidirectional Sanger sequencing of genes important for long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome type 1 (BrS1), and catecholaminergic polymorphic ventricular tachycardia (CPVT) (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and RYR2) was performed. Multiplex ligation-dependent probe amplification (MLPA) was used to detect large deletions or duplications in the LQTS genes. Six pathogenic sequence variants (four LQTS and two CPVT) were discovered in 15 SUD cases (40 %). Ten first-degree family members were found to be mutation carriers (seven LQTS and three CPVT).ConclusionCardiac ion channel genetic testing in autopsy-negative sudden death victims has a high diagnostic yield, with identification of the disease in 40 % of families. First-degree family members should be offered predictive testing, clinical evaluation, and treatment with the ultimate goal to prevent sudden death.

Post-mortem Whole exome sequencing with gene-specific analysis for autopsy-negative sudden unexplained death in the young: a case series.

Annually, thousands of sudden deaths in individuals under 35 years remain unexplained following comprehensive medico-legal autopsy. Previously, post-mortem genetic analysis by Sanger sequencing of four major cardiac channelopathy genes revealed that approximately one-fourth of these autopsy-negative sudden unexplained death in the young (SUDY) cases harbored an underlying mutation. However, there are now over 100 sudden death-predisposing cardiac channelopathy-, cardiomyopathy-, and metabolic disorder-susceptibility genes. Here, we set out to determine whether post-mortem whole exome sequencing (WES) is an efficient strategy to detect ultra-rare, potentially pathogenic variants. We performed post-mortem WES and gene-specific analysis of 117 sudden death-susceptibility genes for 14 consecutively referred Caucasian SUDY victims (average age at death 17.4 ± 8.6 years) to identify putative SUDY-associated mutations. On average, each SUDY case had 12,758 ± 2,016 non-synonymous variants, of which 79 ± 15 localized to these 117 genes. Overall, eight ultra-rare variants (seven missense, one in-frame insertion) absent in three publically available exome databases were identified in six genes (three in TTN, and one each in CACNA1C, JPH2, MYH7, VCL, RYR2) in seven of 14 cases (50 %). Of the seven missense alterations, two (T171M-CACNA1C, I22160T-TTN) were predicted damaging by three independent in silico tools. Although WES and gene-specific surveillance is an efficient means to detect rare genetic variants that might underlie the pathogenic cause of death, accurate interpretation of each variant is challenging. Great restraint and caution must be exercised otherwise families may be informed prematurely and incorrectly that the root cause has been found.

Abstract 15841: Whole Exome Sequencing and Analysis for Sudden Unexplained Death in the Young: A Case Series

Introduction: Annually, thousands of sudden deaths in individuals under the age of 35 years remain unexplained following a medico-legal autopsy and are termed autopsy negative sudden unexplained death in the young (SUDY). Cardiomyopathies, channelopathies, and metabolic disorders may underlie a significant number of SUDY cases. Previously, we demonstrated that 25% of autopsy-negative SUDY cases had mutations in the 4 major cardiac ion channel genes ( KCNQ1, KCNH2, SCN5A , and RYR2 ). However, over 100 sudden death-susceptibility genes have been discovered and may be implicated in SUDY. Objective: We explored the utility of whole exome sequencing (WES) followed by gene-specific surveillance as an efficient and effective means of performing post-mortem genetic testing in SUDY. Methods: Postmortem WES was performed on 14 consecutively-referred white SUDY victims (57% men; average age at death 17.4 ± 8.6 years) using the Agilent SureSelect Human All Exon V4+UTR capture kit and an Illumina HiSeq 2000 sequencer. Following variant alignment (hg19) and annotation, 117 cardiac channelopathy-, cardiomyopathy-, and metabolic disorder-susceptibility genes were surveyed to identify putative SUDY-associated mutations. Potentially pathogenic variants had to be non-synonymous and ultra-rare [i.e. absent in all 3 evaluated exome databases (1,000 Genome Project, the NHLBI GO Exome Sequencing Project, and Exome Chip Design)]. Results: On average, each SUDY case had 12,758 ± 2016 non-synonymous variants, of which 79 ± 15 localized to the 117 evaluated genes. Overall, 8 unique, ultra-rare variants (7 missense, 1 in-frame insertion) identified in 6 genes (3 in TTN ; 1 each in CACNA1C, JPH2, MYH7, VCL, RYR2 ) were detected in 7 of 14 cases (50%). Of the 7 missense alterations, 2 (T171M- CACNA1C , I22160T- TTN ) were predicted damaging by 3 in-silico tools. Conclusions: Although WES and gene-specific surveillance is an efficient and effective strategy to detect rare, potentially lethal, genetic variants, the accurate interpretation of each variant is daunting. Importantly, rarity, even ultra-rarity, does not equal pathogenicity even when the ultra-rare variant resides within a so-called sudden death-susceptibility gene.

Pathogeneses of Sudden Cardiac Death in National Collegiate Athletic Association Athletes

The pathogenesis of sudden cardiac death in college athletes has not been defined by systematic case identification. A total of 45 cases of sudden cardiac death were identified in National Collegiate Athletic Association (NCAA) athletes from 2004 to 2008 based on an internal reporting system and review of media reports. Autopsy reports were reviewed and adjudicated by a multidisciplinary panel. Cause of death could be reasonably determined in 36 cases; 3 athletes had no autopsy, 5 autopsy reports could not be obtained, and 1 autopsy had insufficient information to determine cause of death. The most common finding at death was a structurally normal heart or autopsy-negative sudden unexplained death (11, 31%), followed by coronary artery abnormalities (5, 14%), dilated cardiomyopathy (3, 8%), myocarditis related (3, 8%), aortic dissection (3, 8%), and idiopathic left ventricular hypertrophy/possible hypertrophic cardiomyopathy (HCM; 3, 8%). There was 1 case each (3%) of hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, commotio cordis, and Kawasaki disease. There was 1 case of death in a sickle cell positive athlete who also had left ventricular hypertrophy. The adjudicated diagnosis agreed with the official pathology report in only 59% of cases. Unexplained death with a structurally normal heart is the most common finding after suspected sudden cardiac death in NCAA athletes. Hypertrophic cardiomyopathy is infrequently seen, and conclusions in autopsy reports may not accurately reflect the pathological findings. Standardized protocols for cardiovascular autopsies in athletes are needed, including postmortem genetic testing, particularly in autopsy-negative cases.

Familial cardiological and targeted genetic evaluation: Low yield in sudden unexplained death and high yield in unexplained cardiac arrest syndromes

It has been reported that cardiological screening and genetic evaluation in relatives of families with sudden unexplained death syndrome and unexplained cardiac arrest (UCA) may uncover a heritable etiology in a significant proportion of families. To evaluate the yield of a comprehensive evaluation protocol of a large unselected cohort of consecutive families with autopsy-negative sudden unexplained death syndrome (termed sudden arrhythmic death syndrome [SADS]) and UCA. We studied (1) 109 consecutive families (411 relatives) referred with 1 or more sudden deaths in the family and (2) 52 consecutive probands with UCA (91 relatives) referred by cardiologists between January 2007 and December 2012. A comprehensive cardiological screening was performed followed by targeted genetic evaluation if a clinical phenotype was proven or suspected. Diagnosis was made by a multidisciplinary team using published clinical criteria. A diagnosis was made in 19 of 109 families with SADS (yield 18%), with the majority having long QT syndrome (LQTS). Diagnosis varied according to proband age, with LQTS most common in the very young (≤20 years) and Brugada syndrome in the older age probands (≥40 years) (P = .03). In contrast, a diagnosis was made in 32 of 52 families with UCA (yield 62%), the majority of which had LQTS and Brugada syndrome. No clinical or circumstantial factors increased the likelihood of diagnosis in families with either SADS or UCA. In contrast to previously published series, a comprehensive strategy of cardiological evaluation and targeted genetic testing in more than 100 families with SADS was found to have a lower diagnostic yield (18%). Diagnostic yield in families with UCA was approximately 4 times higher (62%), which is consistent with the published literature.