Negative Autopsy Research Articles

Implications of age and sex on the diagnostic yield of sudden arrhythmic death syndrome

Abstract Introduction Sudden arrhythmic death syndrome (SADS) refers to an unexplained sudden death with a negative autopsy. An inherited cardiac condition (ICC) may be diagnosed through familial clinical evaluation (FE) or post-mortem genetic testing (molecular autopsy [MA]) or both. We aimed to investigate the impact of age and sex of SADS decedents on the diagnostic yield and aetiology to facilitate a targeted approach to management. Methods Consecutive referrals to a single centre for FE only, MA only or both, following a SADS death were included. First-degree family members underwent comprehensive FE. A panel of 36 cardiac genes was sequenced for MA. A post-mortem diagnosis could be obtained by either FE, MA or both. A Bayesian framework for analysis was performed to identify associations. Results Seven-hundred-and-sixty SADS decedents (66% male; mean age 31±12 years) were investigated. The overall diagnostic yield for an ICC was 37% (32-42%) and 9% (6-12%) for FE and MA cohorts, respectively. In a subset where both MA and FE were performed the diagnostic yield was 45% (38-61%). For each year increase in age, the relative risk of an FE diagnosis of long QT syndrome (LQTS) or Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) versus remaining unexplained declined by 5.6% (RR 0.94 [0.91-0.98]) and by 11% (RR 0.89 [0.81-0.97]), respectively. Females were more likely to have a diagnosis compared with males by both FE (40% [34-45%] vs 36% [31-41%]) and MA (15% [10-21%] vs 6% [3-8%]). Females (8.1% [4.1-13.4%)], were more likely to be diagnosed with LQTS than males (1.2% [0.2-2.7%]) in the MA cohort. Conclusions After a SADS death, the diagnostic yield of comprehensive FE, MA or both in an expert setting can be up to 45%. Younger age of death is associated with greater likelihood of LQTS and CPVT diagnosis with the highest yield in children and adolescents. Female sex in SADS decedents is associated with a higher yield of LQTS in MA. These data highlight the relative utility of FE and MA depending on age and sex for determining underlying diagnoses following SADS deaths.

Analysis of Forensic Death Statistics From 2013 to 2022 and Autopsy Practices in Türkiye

Autopsy rates are significantly lower that what they should be worldwide. Additionally, autopsy practices vary between countries. To examine the autopsy rates, the distribution and temporal changes of forensic autopsy cases, so as to identify the areas in the death investigation system that require improvement in Türkiye. Cross-sectional study. “Forensic Death Examination Statistics” of the Council of Forensic Medicine (CFM) and “Death Statistics” of the Turkish Statistical Institute were compared and analyzed for the years 2013-2022 in Türkiye. The number of forensic death cases sent to the CFM has increased over time. For all causes of deaths, the autopsy rate is approximately 3.6-4.8%. The cause-specific mortality rates for deaths due to sharp instrument trauma, blunt trauma, occupational accident, undetermined, and poisoning have increased over the years. “The percentage of “undetermined” deaths, which are important to demonstrate negative autopsies, was 14.2% in 2021. Although the autopsy rates have slightly increased in a volatile trend over time in Türkiye, they are still not at the desired level. Thus, it is essential to further raise awareness among all professionals involved in death investigations about the importance of autopsies.

From Death to Life/Back to the Future: Detailed Premorbid Clinical and Family History Can Save Lives and Address the Final Diagnosis in Sudden Unexplained Deaths With Negative Autopsy.

Sudden cardiac death is a sudden, unexpected death developed by one of the many different causes of cardiac arrest that occur within 1 hour of the onset of new symptoms. Sudden unexplained death (SUD) comprises a normal heart at postmortem examination and negative toxicological analysis. SUD often arises from cardiac genetic disease, particularly channelopathies. Channelopathies, or inherited arrhythmia syndromes, are a group of disorders characterized by an increased risk of sudden cardiac death, abnormal cardiac electrical function, and, typically, a structurally normal heart. They share an underlying genetic etiology where disease-causing genetic variants may lead to the absence or dysfunction of proteins involved in the generation and propagation of the cardiac action potential. Our study aimed to evaluate the importance of next-generation sequencing in the postmortem investigations of SUD cases. In this study, 5 forensic SUD cases were investigated for inherited cardiac disorders. We screened a total of 68 cardiac genes for the sibling of case 1, as well as case 2, and 51 genes for cases 3, 4, and 5. Of the 12 variants identified, 2 likely pathogenic variants (16.7%) were the TMEM43 _ c.1000+2T>C splice site mutation and the SCN5A _ p.W703X nonsense mutation. The remaining 10 variants of uncertain significance were detected in the TRPM4 , RANGRF , A KAP9 , KCND3 , KCNE1 , DSG2 , CASQ1 , and SNTA1 genes. Irrespective of genetic testing, all SUD families require detailed clinical testing to identify relatives who may be at risk. Molecular autopsy and detailed premorbid clinical and family histories can survive family members of SUD cases.

Profile of autopsy cases at tertiary care centre during pandemic

The profile of autopsy cases are necessary for taking necessary preventive measures in future. New civil hospital is a government tertiary care center in south Gujarat where annually approximately 2500 cases are brought for postmortem examination. Forensic medicine department conducts postmortem examination of expert level cases which are directly brought by investigating officer or referred from medical officers. Manner of death is very important to determine the nature of investigation. The present study is a retrospective study. It includes all the total 131 expert autopsy cases conducted from 1 Jan 2020 to 31 Dec 2020. The emphasis was given on age, sex, cause of death, manner of death, mode of death, causative weapons. All these data were collected and analyzed. In the year 2020 total 131 expert cases out of them 89 male, 41 female and 1 unknown. Among them mode of death 26.72 % asphyxia, 20.61% coma, 33.59% syncope, 9.16% pending and 9.92% undetermined, 48.09% homicidal, 14.5% suicidal, 6.11% accidental, 12.98% natural death cases, 9.92% negative autopsy, 15.26% cases the time since death was within 12 hours. Present study evaluates the expert and referred autopsy cases conducted in a tertiary center, majority of the cases are of allegation and highly suspicious nature. So very few cases of road traffic accident and natural deaths or obvious suicidal death cases are brought to our department. So sometimes it becomes a challenging work to determine manner of the death, causative weapon and time since death.

Histopathological Features of Skin changes caused by Electrocution: An Autopsy study

BACKGROUND: Dependency to electrical equipments and improper safety measures has led to a significant increase in deaths due to electrocution. Confirming the cause of death in electrocution is one of the biggest challenges. Skin is the most frequently involved tissue in electrocution and histopathology of skin from electric marks aids in proper diagnosis. OBJECTIVES: To study the histomorphological features of epidermis and dermis in skin tissue of entry and exit wounds in electrocution deaths. MATERIAL AND METHODS: This is an observational study done over a period of one year. Skin biopsy from medico legal autopsy of non-lightening electrocution deaths obtained from entry or exit wound site were included for the study. Gross and histopathological details were studied and data analyzed. RESULTS: Significant gross features were surface discoloration of skin 16 (61%) and ulceration 05 (20%). Microscopic features were coagulative necrosis 21 (80.7%), dermo-epidermal separation 20 (80.7%), focal ulceration of epithelium 05 (19%), clefting of epidermis (60%), streaming of nuclei (92.3%), elongation of nuclei (92.3%) and microblisters 02 (15.3%). CONCLUSION: One of the important causes of negative autopsy is electrocution deaths. In such cases dermatopathology is a diagnostic tool coupled with circumstantial evidence. Histological hallmark of electrocution skin injury is epidermal nuclear elongation.

Molecular autopsy: Twenty years of post-mortem diagnosis in sudden cardiac death.

In the forensic medicine field, molecular autopsy is the post-mortem genetic analysis performed to attempt to unravel the cause of decease in cases remaining unexplained after a comprehensive forensic autopsy. This negative autopsy, classified as negative or non-conclusive, usually occurs in young population. In these cases, in which the cause of death is unascertained after a thorough autopsy, an underlying inherited arrhythmogenic syndrome is the main suspected cause of death. Next-generation sequencing allows a rapid and cost-effectives genetic analysis, identifying a rare variant classified as potentially pathogenic in up to 25% of sudden death cases in young population. The first symptom of an inherited arrhythmogenic disease may be a malignant arrhythmia, and even sudden death. Early identification of a pathogenic genetic alteration associated with an inherited arrhythmogenic syndrome may help to adopt preventive personalized measures to reduce risk of malignant arrhythmias and sudden death in the victim's relatives, at risk despite being asymptomatic. The current main challenge is a proper genetic interpretation of variants identified and useful clinical translation. The implications of this personalized translational medicine are multifaceted, requiring the dedication of a specialized team, including forensic scientists, pathologists, cardiologists, pediatric cardiologists, and geneticists.

Postmortem Genetic Testing in Sudden Unexpected Death: A Narrative Review.

Sudden unexpected death (SUD) is one of the challenging situations encountered in forensic medicine. As a rule, a comprehensive forensic assessment is performed to identify the cause of death in such cases; however, the absence of findings suggestive of a cause, i.e., a negative autopsy, warrants further investigation such as a molecular autopsy. In this review, we aim to highlight the genetic causes of SUD, tools used in a molecular autopsy, and the role of screening in surviving relatives. As per several guidelines, the most preferred samples for DNA extraction are whole blood and fresh frozen tissues. Furthermore, Sanger sequencing and next-generation sequencing are the technologies that are used for genetic analysis; the latter overcomes the former's drawbacks in terms of cost-effectiveness, time consumption, and the ability to sequence the whole exome. SUD have diverse etiologies; we can generally classify them into cardiac and non-cardiac causes. Regarding cardiac causes, many conditions having an underlying genetic basis are included, such as channelopathies and cardiomyopathies. Regarding non-cardiac causes of SUD, the main etiologies are epilepsy and metabolic disorders. Nevertheless, it has been proposed that there is a genetic overlap between channelopathies, especially long QT syndromes and epilepsy. Additionally, fatty acid oxidation disorders are major metabolic conditions that are caused by certain genetic mutations that can lead to SUD in infancy. Since many SUD causes have an underlying genetic mutation, it is important to understand the genetic variations not only to recognize the cause of death but also to undertake further preventive measures for surviving relatives. In conclusion, a molecular autopsy has a major role in the forensic examination of cases of SUD.

The definitive indefinite cause of death Case series based Evaluation and discussion of Negative and Obscure Autopsy

Medicolegal autopsies are routinely done by forensic pathologist to fulfil the objectives of autopsy and to solve the dilemma of investigating agencies. But the medicolegal autopsy is not always concluding the main objective of it which is cause of death and such autopsies are categorised as obscure and negative autopsy. Acknowledgement of incidence of negative autopsy to the practicing forensic pathologist is necessary. We are discussing here some autopsies conducted by the author(s) after which the final scientific cause of death could not be ascertained. The algorithm-based approach toward the determination of cause of death and importance of other circumstantial evidences has been discussed.

Gross and Histopathological Study of Adrenal Glands from Routine Medico legal Autopsies

Background: Autopsies are important in clinical medicine as they can identify medical errors and assist incontinuous improvement. The role of a forensic pathologist is highly significant in determining the cause of deathas an undiagnosed case can contribute to the improvement of clinical or surgical management of such type ofpatients, and help prevent unexpected deaths in the future. In an era, where pathological autopsies are limited,the medico-legal autopsy will serve as supplement to document the incidental adrenal pathologies in the studypopulation.Material and Methods: The prospectivestudy was performed after getting proper approval from Institute ethicalcommittee. The adrenal glands were procured from medico-legal autopsies conducted from 2019 -2021, at themortuary of Govt. Medical College and Hospital, Aurangabad. All the necessary details were noted from thepolice requisition, Inquest panchnama and clinical papers provided. All the important findings were noted downin the predesigned case record form.Result: A total of 128 adrenal glands were examined for gross and histopathological changes. The number of malesand females studied comprised of 38 males (59 %) and 26 females (41%). Majority of lesions were observed onhistopathology as compared to gross examination. Maximum number of the lesions were observed in the age groupbetween 21 to 30 years (29%). Gross adrenal lesions were noted in 62% males and 38% females. Histopathologylesions were noted in 63% males and 37% females. The study showed more of unnatural cases than natural cases.Majority of the lesions are seen in unnatural deaths than natural deaths except enlarged adrenals are found innatural deaths. Majority of the adrenal histopathology lesions were found in unnatural deaths except adrenalitis,hypertrophy and atrophy which is common in natural deaths. Majority of the lesions are found in unnaturaldeaths both on gross 73% as well as histopathological 67% examination.Conclusion: This study emphasizes the importance of Gross as well as Histopathological examination in medicolegalautopsies. In cases of negative autopsies, this necessitates to examine the adrenal glands, histopathologically whichmay give a clue about the cause of death.

An experimental rat model of electric shock injury with isolated electric shock and water conduction: the histopathological changes on the skin and internal organs and the effect on biochemical parameters.

It is difficult to determine the cause of death in electric shock injuries when no trace can be determined on the skin, and this is accepted as a reason for negative autopsy. We aimed to determine useful parameters in the definition of the cause of deaths associated with electric shock and particularly those formed with water conduction. This study used a total of 42 rats, applied with fatal electric shock formed of isolated electric shock at 220V and with water conduction. The serum NT-ProBNP and H-FABP levels were examined together with histopathological changes in the brain, cerebellum, brainstem, heart, liver and skin and the Bax, caspase-3 and HSP-60 antibody status in these tissues. A statistically significant difference was determined between the groups in respect of the serum H-FABP values and the immunohistochemical staining of the samples taken from the organs. In conclusion, this study is the first in literature with an experimental model of electric shock with water conduction. Using immunohistochemical and biochemical markers in deaths associated with isolated electric shock and electric shock with water conduction, the results of this study can contribute to the clarification of one of the reasons for negative autopsy in forensic medicine.

Burden of sudden cardiac death in persons aged 1-40 years in the Czech Republic.

The aim of the study was to ascertain the incidence, circumstances and causes of sudden cardiac death in persons aged 1-40 years in the Czech Republic. De-identified autopsy reports of all individuals who died suddenly between the ages of 1-40 years during the period 2014-2019 inclusive in a selected area of the Czech Republic were analysed retrospectively. Persons with substantial cardiovascular pathology defined by histopathological criteria and those with a negative autopsy were included in the study. The latter were designated as sudden arrhythmic death syndrome. In total, 245 sudden cardiac death cases were identified resulting in an incidence rate of 2.4/100,000 person-years. Among the deceased, we found an enormous gender gap with men representing 81% of cases. More than 80% of deaths occurred during everyday activities or sleep, whereas only 7% were sports-related. The most common cause of death was coronary artery disease detected in 38%, which was followed by cardiomyopathies in 15%, sudden arrhythmic death syndrome in 12%, left ventricular hypertrophy in 10%, and congenital heart defects in 7%. Coronary artery disease is the predominant cause of sudden cardiac death in the young population of the Czech Republic. Hence, effective preventive measures targeted at the reduction of risk factors associated with early coronary artery disease should be reinforced. The second most prevalent cause in our population are potentially heritable heart conditions such as cardiomyopathies and sudden arrhythmic death syndrome. This fact has already prompted the introduction of molecular autopsy and cardiogenetic care for relatives in the Czech Republic.

Histomorphological changes of skin in electrocution deaths - A study in a tertiary care hospital

Electrocution deaths (EDs) is one of the important causes of negative autopsy with no gross pathological findings in almost half of all cases. The history surrounding the cause of death and circumstantial evidence is sometimes ambiguous and poses great difficulty. Hence, this need to be coupled with histopathological examination to arrive at the diagnosis.: Retrospective study was conducted with entry and exit wound of skin samples among 17 cases of EDs Total- 46 skin samples. Corresponding normal skin was used as control. The histomorphological changes of skin were noted in both entry and exit wound separately and its association with electrical voltage was studied and statistically analysed.: The maximum EDs were due to high voltage (47.06%) at the workplace (70.5%) and were accidental in nature (100%) predominantly affecting males (88.24%). Upper extremity was the chief area of wounding (51.7%). Most common gross abnormality was ulcer/crater (82%) in entry wound followed by bulla formation (70%). Commonly exit wound showed splits in skin (75%). The most common histopathological finding in entry as well as exit wound was dermoepidermal separation (88%, 75%), coagulative necrosis of epidermis (82%, 66%) and nuclear streaming (76%, 50%) respectively. : Histopathological changes in skin give the supportive evidence in determining the cause of death especially in case of negative autopsy. The important microscopic features of electrocution are dermoepidermal separation, coagulative necrosis, and nuclear streaming.

MiR-3113-5p, miR-223-3p, miR-133a-3p, and miR-499a-5p are sensitive biomarkers to diagnose sudden cardiac death

BackgroundSudden cardiac death (SCD) remains a great health threat and diagnostic challenge, especially those cases without positive autopsy findings. Molecular biomarkers have been urgently needed for the diagnosis of SCD displaying negative autopsy results. Due to their nature of stability, microRNAs (miRNAs) have emerged as promising diagnostic biomarkers for cardiovascular diseases.MethodsThis study investigated whether specific cardio-miRNAs (miR-3113-5p, miR-223-3p, miR-499a-5p, and miR-133a-3p) could serve as potential biomarkers for the diagnosis of SCD. Thirty-four SCD cases were selected, 18 categorized as SCD with negative autopsy (SCD-negative autopsy) findings and 16 as SCD with positive autopsy (SCD-positive autopsy) findings such as coronary atherosclerosis and gross myocardial scar. Carbon monoxide (CO) intoxication (n = 14) and fatal injury death (n = 14) that displayed no pathological changes of myocardium were selected as control group, respectively. Histological analyses were performed to reveal the pathological changes and real-time quantitative polymerase chain reaction (RT-qPCR) was used to determine the expression of those miRNAs.ResultsIt showed that heart samples from the SCD-negative autopsy group displayed no remarkable difference with regard to the expression of cleaved-caspase3, CD31, and CD68 and the extent of fibrotic tissue accumulation when compared with control samples. The four cardio-miRNAs were significantly up-regulated in the SCD samples as compared with control. When discriminating SCD from controls, receiver operating characteristic (ROC) curve analysis revealed that the areas under the curve (AUC) of these 4 miRNAs were from 0.7839 to 0.9043 with sensitivity of 64.71–97.06% and specificity of 70–100%. Moreover, when discriminating the specific causes of SCD, the four miRNA expressions increased in the heart from the SCD-negative autopsy group as relative to that from the SCD-positive autopsy group, and a combination of two miRNAs presented higher diagnostic value (AUC = 0.7407–0.8667).ConclusionmiR-3113-5p, miR-223-3p, miR-499a-5p, and miR-133a-3p may serve as independent diagnostic biomarkers for SCD, and a combination of two of these miRNAs could further discriminate detailed causes of SCD.

B-PO02-014 PLN VARIANTS IN PATIENTS WITH SUDDEN CARDIAC ARREST/DEATH WITHOUT DILATED OR ARRHYTHMOGENIC CARDIOMYOPATHY: A CASE SERIES

Phospholamban, encoded by the PLN gene, is a regulator of intracellular Ca2+. Pathogenic PLN variants cause cardiac remodeling and early death. It is plausible that PLN variants confer a pro-arrhythmic phenotype without overt structural remodeling. To date, most PLN variants associated with sudden cardiac arrest/death (SCA/D) are accompanied by structural cardiomyopathies. The prevalence of PLN variants in autopsy-negative SCA/D cases without overt cardiomyopathy is unclear. We present a case series of patients with PLN gene variants identified due to SCA/D without overt dilated or arrhythmogenic cardiomyopathies. We describe PLN gene variants presenting with primarily arrhythmic phenotypes. The PLN gene should be strongly considered in genetic testing strategies for SCA/D. Cases were ascertained through professional collaboration among cardiovascular genetic counselors. We prioritized cases with PLN variants presenting without recognized cardiomyopathy phenotypes and/or in autopsy-negative SCA/D. We describe five cases with pathogenic PLN variants. Two are previously reported (p.Arg14del, p.Leu39Ter), and one is novel (p.Gln22LeufsX19). There were 3 pediatric cases and 2 adult cases, and 2/3 pediatric cases presented with SCD and negative autopsies. The other pediatric case survived SCA, but follow-up cardiac investigations were normal. Four of five cases had uninformative cardiac phenotypes, though one case had some evidence of cardiac hypertrophy at autopsy. Interestingly, 4/5 cases had SCA/D occur during rest, and 1/5 cases occurred with some activity. Last, one adult with SCD had a history atrial fibrillation, though no other cases had known arrhythmias. Table 1 summarizes these findings for comparison and contrast. With a role in Ca2+ regulation, it is plausible that PLN variants confer a pro-arrhythmic substrate and increased of SCA/D in the absence of cardiomyopathy. We raise awareness for the possible role of PLN variants in phenotype- and autopsy-negative SCA/D and encourage further investigation. This may help guide genetic counseling for PLN variants found in patients at autopsy and/or in patients who have not yet developed cardiomyopathy.

Prevented Sudden Cardiac Death and Neurologic Recovery in Inherited Heart Diseases.

Introduction: Inherited cardiovascular diseases are an important cause of sudden cardiac death (SD). The use of risk scores identify high risk patients who would benefit from an implantable cardioverter-defibrillators (ICDs). The development of automated devices for out-of-hospital cardiac arrest improves early resuscitation. The objective of the study is to quantify prevented SD and the neurological recovery of patients with inherited cardiovascular diseases.Methods: Two hundred fifty-seven cases of SD (age 42 ± 18 years, 79.4% men) of non-ischemic cardiac cause were prospectively collected during the study period (2009–17). Fifty three (20.6%) had a resuscitated cardiac arrest (RCA) (age 40 ± 18 years, 64.2% male). Epidemiological, clinical and autopsy aspects were analyzed. Prevented SD was defined as a combination of RCA and appropriate ICD therapy cases.Results: An autopsy was performed in 157/204 (77.0%) cases who died. There were 19 (12.1%) cases with a negative autopsy. The diagnosis of cardiomyopathy and channelopathy was 58.0 and 18.7%, respectively. Female sex and confirmed or suspected channelopathy were associated with successful resuscitation. The percentage of prevented SD remained low during the study period (mean 35.6%). 60.4% of RCA cases presented good neurological outcome. There was no association between neurological recovery and therapeutic hypothermia, but there was association with time of resuscitation (min).Conclusion: A fifth part of non-ischemic cardiac arrests were resuscitated. Female sex and channelopathies were more prevalent among RCA. Two thirds of RCA had a good neurological recovery.

Autopsy study of sudden cardiac death

BackgroundThe causes of sudden cardiac death are undetected despite detailed postmortem examination, histological examination and toxicological analysis leading to negative autopsy in some cases. The present study is carried out with a view to evaluate the victims of sudden cardiac death (SCD) brought for medicolegal autopsy.The present cross sectional study included 74 cases of sudden cardiac death within 24 hours with history of chest pain or known ischaemic heart disease brought for medicolegal autopsy. During the autopsy, heart and coronaries were dissected to find out any pathology and the subjected for histopathological examination.ResultsThe victims of SCD were mostly males (85.1%) with peak incidence in older ages above 60years (41.9%). Almost 84% of the victims had survival period of less than 6 hours. Left anterior descending artery (64.9%) was the commonest coronary artery involved with atherosclerosis. Most of the victims had double vessel block with 71.6% had coronary narrowing exceeding 75% stenosis. There was statistically significant positive correlation between the coronary block and the age of the victim of sudden cardiac death (p=0.007).Careful and detailed autopsy can be conducted in SCD to find out its cause.

The Postmortem Interpretation of Cardiac Genetic Variants of Unknown Significance in Sudden Death in the Young: A Case Report and Review of the Literature.

Sudden cardiac death (SCD) in adolescents and young adults is a major traumatic event for families and communities. In these cases, it is not uncommon to have a negative autopsy with structurally and histologically normal heart. Such SCD cases are generally attributed to channelopathies, which include long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. Our understanding of the causes for SCDs has changed significantly with the advancements in molecular and genetic studies, where many mutations are now known to be associated with certain channelopathies. Postmortem analysis provides great value in informing decision-making with regard to screening tests and prophylactic measures that should be taken to prevent sudden death in first degree relatives of the decedent. As this is a rapidly advancing field, our ability to identify genetic mutations has surpassed our ability to interpret them. This led to a unique challenge in genetic testing called variants of unknown significance (VUS). VUSs present a diagnostic dilemma and uncertainty for clinicians and patients with regard to next steps. Caution should be exercised when interpreting VUSs since misinterpretation can result in mismanagement of patients and their families. A case of a young adult man with drowning as his proximate cause of death is presented in circumstances where cardiac genetic testing was indicated and undertaken. Eight VUSs in genes implicated in inheritable cardiac dysfunction were identified and the interpretation of VUSs in this scenario is discussed.

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.

MOLECULAR AUTOPSY: EVALUATION OF SUDDEN UNEXPECTED DEATH CASES IN TERMS OF “KCNQ1” GENETIC VARIATION

Background: Deaths occuring without a known disease and/or a known cause, deaths with non-lethal diseases are interpretated as sudden-unexpected-suspected deaths. Autopsy should always required to evaluate the cause of death. Some of the cases can be termed as negative autopsy since the cause of death can not be determined. This is one of the main interests of the future forensics. Molecular autopsies are one of the main practices of to reduce the negative autopsy ratios. Thus, post-mortem KCNQ1 genetic variation tests are done in sudden unexpected death cases.&#x0D; Material and methods: In this study 0 – 50 years old sudden-unexpected deaths autopsy cases were handled. Samples taken from cases were evaluated and “KCNQ1” genetic variation tests were done in our Department.&#x0D; Results: This study included 47 cases of 42 sudden unexpected death cases (0 – 50 age group) and 5 control group. 15 cases were between 40 – 50 age group and number of cases were increasing with age. 29 of cases (% 69) were male. Evaluation of body-mass index of cases were done and normal weighted cases were the most common with 21 cases (% 50). According to death locations; 17 cases had died (% 45,9) at home. Death location records of 5 cases couldn’t be found. Pathological examinations of all cases were done. We had identified fibrosis and fatty change appearances in SA node of 9 cases (% 21,4) and AV node of 13 cases (% 30,9) especially in conduction tissue examinations. As the result of KCNQ1 genetic analysis of cases, we identified sequence variations in 1638th nucleotid of exon 13 and 1986th nucleotid of exon 16.&#x0D; Conclusion: Cases with conduction system pathology and sequence variations of KCNQ1 genetic analysis shows that we are in need of these tests among routine practice to reduce negative autopsy ratios.&#x0D; Key words: KCNQ1, molecular autopsy, sudden unexpected death, conduction system, negative autopsy.

Sudden arrhythmia death syndrome in young victims: a five-year retrospective review and two-year prospective molecular autopsy study by next-generation sequencing and clinical evaluation of their first-degree relatives.

Sudden arrhythmia death syndrome (SADS) accounts for about 30% of causes of sudden cardiac death (SCD) in young people. In Hong Kong, there are scarce data on SADS and a lack of experience in molecular autopsy. We aimed to investigate the value of molecular autopsy techniques for detecting SADS in an East Asian population. This was a two-part study. First, we conducted a retrospective 5-year review of autopsies performed in public mortuaries on young SCD victims. Second, we conducted a prospective 2-year study combining conventional autopsy investigations, molecular autopsy, and cardiac evaluation of the first-degree relatives of SCD victims. A panel of 35 genes implicated in SADS was analysed by next-generation sequencing. There were 289 SCD victims included in the 5-year review. Coronary artery disease was the major cause of death (35%); 40% were structural heart diseases and 25% were unexplained. These unexplained cases could include SADS-related conditions. In the 2-year prospective study, 21 SCD victims were examined: 10% had arrhythmogenic right ventricular cardiomyopathy, 5% had hypertrophic cardiomyopathy, and 85% had negative autopsy. Genetic analysis showed 29% with positive heterozygous genetic variants; six variants were novel. One third of victims had history of syncope, and 14% had family history of SCD. More than half of the 11 first-degree relatives who underwent genetic testing carried related genetic variants, and 10% had SADS-related clinical features. This pilot feasibility study shows the value of incorporating cardiac evaluation of surviving relatives and next-generation sequencing molecular autopsy into conventional forensic investigations in diagnosing young SCD victims in East Asian populations. The interpretation of genetic variants in the context of SCD is complicated and we recommend its analysis and reporting by qualified pathologists.