Sudden Unexplained Death Research Articles

Exome analysis focusing on epilepsy-related genes in children and adults with sudden unexplained death

PurposeGenetic studies in sudden infant death syndrome (SIDS) and sudden unexplained death (SUD) cohorts have indicated that cardiovascular diseases might have contributed to sudden unexpected death in 20–35 % of autopsy-negative cases. Sudden unexpected death can also occur in people with epilepsy, termed as sudden unexpected death in epilepsy (SUDEP). The pathophysiological mechanisms of SUDEP are not well understood, but are likely multifactorial, including seizure-induced hypoventilation and arrhythmias as well as genetic risk factors. The sudden death of some of the SIDS/SUD victims might also be explained by genetic epilepsy, therefore this study aimed to expand the post-mortem genetic analysis of SIDS/SUD cases to epilepsy-related genes. MethodsExisting whole-exome sequencing data from our 155 SIDS and 45 SUD cases were analyzed, with a focus on 365 epilepsy-related genes. Nine of the SUD victims had a known medical history of epilepsy, seizures or other underlying neurological conditions and were therefore classified as SUDEP cases. ResultsIn our SIDS and SUD cohorts, we found epilepsy-related pathogenic/likely pathogenic variants in the genes OPA1, RAI1, SCN3A, SCN5A and TSC2. ConclusionPost-mortem analysis of epilepsy-related genes identified potentially disease-causing variants that might have contributed to the sudden death events in our SIDS/SUD cases. However, the interpretation of identified variants remains challenging and often changes over time as more data is gathered. Overall, this study contributes insight in potentially pathophysiological epilepsy-related mechanisms in SIDS, SUD and SUDEP victims and underlines the importance of sensible counselling on the risk and preventive measures in genetic epilepsy.

A Systematic Approach to Evaluate Sudden Unexplained Death in Children

To evaluate in the Netherlands the national outcomes in providing cause of and insights into sudden and unexplained child deaths among children via the Postmortem Evaluation of Sudden Unexplained Death in Children (PESUDY) procedure. Suddenly deceased children aged 0-18 years in the Netherlands were included in the PESUDY procedure if their death was unexplained and their parents gave consent. The PESUDY procedure consists of pediatric and forensic examination, biochemical, and microbiological tests; radiological imaging; autopsy; and multidisciplinary discussion. Data on history, modifiable factors, prior symptoms, performed diagnostics, and cause of death were collected between October 2016 and December 2021. 212 cases (median age 11 months, 56% boys, 33% comorbidity) were included. Microbiological, toxicological, and metabolic testing was performed in 93%, 34% and 32% of cases. In 95% a CT scan or MRI was done and in 62% an autopsy was performed. The cause of death was explained in 58% of cases and a plausible cause was identified in an additional 13%. Most children died from infectious diseases. Non-infectious cardiac causes were the second leading cause of death found. Modifiable factors were identified in 24% of non-SIDS/USID cases and mostly involved overlooked alarming symptoms. The PESUDY procedure is valuable and effective for determining the cause of death in children with sudden unexplained deaths and for providing answers to grieving parents and involved health care professionals.

The burden of splice-disrupting variants in inherited heart disease and unexplained sudden cardiac death

There is an incomplete understanding of the burden of splice-disrupting variants in definitively associated inherited heart disease genes and whether these genes can amplify from blood RNA to support functional confirmation of splicing outcomes. We performed burden testing of rare splice-disrupting variants in people with inherited heart disease and sudden unexplained death compared to 125,748 population controls. ClinGen definitively disease-associated inherited heart disease genes were amplified using RNA extracted from fresh blood, derived cardiomyocytes, and myectomy tissue. Variants were functionally assessed and classified for pathogenicity. We found 88 in silico-predicted splice-disrupting variants in 128 out of 1242 (10.3%) unrelated participants. There was an excess burden of splice-disrupting variants in PKP2 (5.9%), FLNC (2.7%), TTN (2.8%), MYBPC3 (8.2%) and MYH7 (1.3%), in distinct cardiomyopathy subtypes, and KCNQ1 (3.6%) in long QT syndrome. Blood RNA supported the amplification of 21 out of 31 definitive disease-associated inherited heart disease genes. Our functional studies confirmed altered splicing in six variants. Eleven variants of uncertain significance were reclassified as likely pathogenic based on functional studies and six were used for cascade genetic testing in 12 family members. Our study highlights that splice-disrupting variants are a significant cause of inherited heart disease, and that analysis of blood RNA confirms splicing outcomes and supports variant pathogenicity classification.

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.

The Association of Nocturnal Seizures and Interictal Cardiac/Central Autonomic Function in Frontal Lobe Epilepsy: Heart Rate Variability and Central Autonomic Network Analysis.

Patients with epilepsy frequently experience autonomic dysfunction, closely related to sudden unexplained death in epilepsy (SUDEP). SUDEP occurs most often at night or during sleep, and frequent nocturnal seizures are an established risk factor. This study investigated the influence of nocturnal seizures on autonomic dysfunction in epilepsy. This retrospective study enrolled frontal lobe epilepsy (FLE) patients who performed 24-hour EEG monitoring. All participants were divided into nocturnal FLE (NFLE, > 90% of seizures occurring during sleep) or diurnal FLE (DFLE) groups. EEG and ECG signals were simultaneously obtained during waking and sleep stages. EEG current density source and connectivity analysis of the autonomic network were performed. ECG was analyzed across time and frequency domains heart rate variability (HRV) analysis method was used. The obtained parameters were compared between the NFLE and DFLE groups. Fifteen NFLE and 16 DFLE patients were enrolled with no significant difference in age, sex, disease duration, seizure frequency, or the number of anti-seizure medications between the two groups. During sleep, a decrease in HRV parameters and an increase of the beta-1 (13-22 Hz) current source density power in the bilateral paracentral lobule (BA4,5,6), precuneus (BA7), and cingulate (BA31) were observed in the NFLE group compared to DFLE group. The NFLE group also showed hyperconnectivity in the central autonomic (12 edges distributed over 10 nodes), sympathetic (2 edges distributed over 3 nodes), and parasympathetic (4 edges distributed over 6 nodes) beta-1 frequency band networks during sleep. During wakefulness, central and cardiac autonomic variables were not significantly different between the NFLE and DFLE groups. Interictal cardiac and central autonomic dysfunction occurred simultaneously and can be attributed to the brain-heart autonomic axis. Our findings suggest that nocturnal seizures may contribute to interictal autonomic dysfunction during sleep in people with epilepsy.

Epidemiology of Sudden Unexplained Death Syndrome among Southeast Asian Labor in Taiwan

Epidemiology of Sudden Unexplained Death Syndrome among Southeast Asian Labor in Taiwan

RyR2 C-terminal truncating variants identified in patients with arrhythmic phenotypes exert a dominant negative effect through formation of wildtype-truncation heteromers.

Gain-of-function missense variants in the cardiac ryanodine receptor (RyR2) are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), whereas RyR2 loss-of-function missense variants cause Ca2+ release deficiency syndrome (CRDS). Recently, truncating variants in RyR2 have also been associated with ventricular arrhythmias (VAs) and sudden cardiac death. However, there are limited insights into the potential clinical relevance and in vitro functional impact of RyR2 truncating variants. We performed genetic screening of patients presenting with syncope, VAs, or unexplained sudden death and in vitro characterization of the expression and function of RyR2 truncating variants in HEK293 cells. We identified two previously unknown RyR2 truncating variants (Y4591Ter and R4663Ter) and one splice site variant predicted to result in a frameshift and premature termination (N4717 + 15Ter). These 3 new RyR2 truncating variants and a recently reported RyR2 truncating variant, R4790Ter, were generated and functionally characterized in vitro. Immunoprecipitation and immunoblotting analyses showed that all 4 RyR2 truncating variants formed heteromers with the RyR2-wildtype (WT) protein. Each of these C-terminal RyR2 truncations was non-functional and suppressed [3H]ryanodine binding to RyR2-WT and RyR2-WT mediated store overload induced spontaneous Ca2+ release activity in HEK293 cells. The expression of these RyR2 truncating variants in HEK293 cells was markedly reduced compared with that of the full-length RyR2 WT protein. Our data indicate that C-terminal RyR2 truncating variants are non-functional and can exert a dominant negative impact on the function of the RyR2 WT protein through formation of heteromeric WT/truncation complex.

Post-mortem genetic analysis of sudden unexplained death in a young cohort: a whole-exome sequencing study.

Sudden unexplained death (SUD) constitutes a considerable portion of unexpected sudden death in the young. Molecular autopsy has proved to be an efficient diagnostic tool in the multidisciplinary management of SUD. Yet, many cases remain undiagnosed using the widely adopted targeted genetic screening strategies. Here, we investigated the genetic substrates of a young SUD cohort (18-40years old) from China using whole-exome sequencing (WES), with the primary aim to identify novel SUD susceptibility genes. Within 255 previously acknowledged SUD-associated genes, 21 variants with likely functional effects (pathogenic/likely pathogenic) were identified in 51.9% of the SUD cases. More importantly, a set of 33 candidate genes associated with myopathy were identified to be novel susceptibility genes for SUD. Comparative analysis of the cumulative PHRED-scaled CADD score and polygenetic burden score showed that the amount and deleteriousness of variants in the 255 SUD-associated genes and the 33 candidate genes identified by this study were significantly higher compared with 289 randomly selected genes. A significantly higher genetic burden of rare variants (MAF < 0.1%) in the 33 candidate genes also highlighted putative roles of these genes in SUD. After incorporating these novel genes, the genetic testing yields of the current SUD cohort elevated from 51.9 to 66.7%. Our study expands understanding of the genetic variants underlying SUD and presents insights that improve the utility of genetic screenings.

Postmortem genetic testing in sudden unexplained death: A public health laboratory experience.

Sudden unexplained death in the young poses a diagnostically challenging situation for practicing autopsy pathologists, especially in the absence of anatomic and toxicological findings. Postmortem genetic testing may identify pathogenic variants in the deceased of such cases, including those associated with arrhythmogenic channelopathies and cardiomyopathies. The Wisconsin State Laboratory of Hygiene (WSLH) is a state-run public health laboratory which performs postmortem genetic testing at no cost to Wisconsin medical examiners and coroners. The current study examines sequencing data from 18 deceased patients (ages 2 months to 49 years, 5 females) submitted to WSLH, from 2016 to 2021. Panel-based analysis was performed on 10 cases, and whole exome sequencing was performed on the most recent 8 cases. Genetic variants were identified in 14 of 18 decedents (77.8%), including 7 with pathogenic or likely pathogenic variants (38.9%). Whole exome sequencing was more likely to yield a positive result, more variants per decedent, and a larger number of variants of uncertain significance. While panel-based testing may offer definitive pathogenic variants in some cases, less frequent variants may be excluded. Whole exome testing may identify rare variants missed by panels, but increased yield of variants of uncertain significance may be difficult to interpret. Postmortem genetic testing in young decedents of sudden unexplained death can provide invaluable information to autopsy pathologists to establish accurate cause and manner of death and to decedent's relatives to allow appropriate management. A public health laboratory model may be a financially advisable alternative to commercial laboratories for medical examiner's/coroner's offices.

Cardiac Genetic Investigation of Sudden Infant and Early Childhood Death: A Study From Victims to Families.

Background Sudden infant death syndrome (SIDS) is the leading cause of death up to age 1. Sudden unexplained death in childhood (SUDC) is similar but affects mostly toddlers aged 1 to 4. SUDC is rarer than SIDS, and although cardiogenetic testing (molecular autopsy) identifies an underlying cause in a fraction of SIDS, less is known about SUDC. Methods and Results Seventy-seven SIDS and 16 SUDC cases underwent molecular autopsy with 25 definitive-evidence arrhythmia-associated genes. In 18 cases, another 76 genes with varying degrees of evidence were analyzed. Parents were offered cascade screening. Double-blind review of clinical-genetic data established genotype-phenotype correlations. The yield of likely pathogenic variants in the 25 genes was higher in SUDC than in SIDS (18.8% [3/16] versus 2.6% [2/77], respectively; P=0.03), whereas novel/ultra-rare variants of uncertain significance were comparably represented. Rare variants of uncertain significance and likely benign variants were found only in SIDS. In cases with expanded analyses, likely pathogenic/likely benign variants stemmed only from definitive-evidence genes, whereas all other genes contributed only variants of uncertain significance. Among 24 parents screened, variant status and phenotype largely agreed, and 3 cases positively correlated for cardiac channelopathies. Genotype-phenotype correlations significantly aided variant adjudication. Conclusions Genetic yield is higher in SUDC than in SIDS although, in both, it is contributed only by definitive-evidence genes. SIDS/SUDC cascade family screening facilitates establishment or dismissal of a diagnosis through definitive variant adjudication indicating that anonymity is no longer justifiable. Channelopathies may underlie a relevant fraction of SUDC. Binary classifications of genetic causality (pathogenic versus benign) could not always be adequate.

Are brief febrile seizures benign? A systematic review and narrative synthesis.

Febrile seizures affect 2%-5% of U.S. children and are considered benign although associated with an increased risk of epilepsy and, rarely, with sudden unexplained death. We compared rates of mortality, neurodevelopmental disorders, and neuropathology in young children with simple and complex febrile seizures to healthy controls. We systematically reviewed studies of 3- to 72-month-old children with simple or complex febrile seizures ≤30 min. We searched studies with outcome measures on mortality, neurodevelopment, or neuropathology through July 18, 2022. Bias risk was assessed per study design. Each outcome measure was stratified by study design. PROSPERO registration is CRD42022361645. Twenty-six studies met criteria reporting mortality (11), neurodevelopment (11), and neuropathology (13), including 2665 children with febrile seizures and 1206 seizure-free controls. Study designs varied: 15 cohort, 2 cross-sectional, 3 case-control, 5 series, and 1 case report. Mortality outcomes showed stark contrasts. Six cohort studies following children after febrile seizure (n = 1348) reported no deaths, whereas four child death series and 1 case report identified 24.1% (108/449) deaths associated with simple (n = 104) and complex (n = 3) febrile seizures ≤30 min. Minor hippocampal histopathological anomalies were common in sudden deaths with or without febrile seizure history. Most electroencephalography (EEG) studies were normal. Neuroimaging studies suggested increased right hippocampal volumes. When present, neurodevelopmental problems usually preexisted febrile-seizure onset. Risk bias was medium or high in 95% (18/19) of cohort and case-control studies vs medium to low across remaining study designs. Research on outcomes after simple or brief complex febrile seizures is limited. Cohort studies suffered from inadequate sample size, bias risk, and limited follow-up durations to make valid conclusions on mortality, neurodevelopment, and neuropathology. Sudden death registries, focused on a very small percentage of all cases, strongly suggest that simple febrile seizures are associated with increased mortality. Although most children with febrile seizures have favorable outcomes, longer-term prospective studies are needed.

Vagal Asystoles in a Boy With Prader-Willi Syndrome.

Prader-Willi syndrome (PWS) is a genetic hormonal disorder of the hypothalamic-pituitary-axis resulting in mental retardation, muscle hypotonia, hypogonadism, and hyperphagia leading to significant obesity. Cardiovascular morbidity and mortality in adult patients with PWS is higher than in healthy controls and mainly secondary to massive obesity. In childhood, mortality may result from respiratory or gastrointestinal illnesses. We present a case of a 10-year-old boy with PWS who experienced recurrent and asymptomatic episodes of sinus pauses caused by the ingestion of large gulps of apple juice, which could be provoked and reproduced. The asystoles could not be provoked by any other vagal maneuvers and an initial diagnostic workup revealed no indication for structural heart disease. Because of the asymptomatic character of the asystoles, no treatment was initially provided. When he re-presented 3 months later after a clinically relevant syncope at school, pacemaker therapy was initiated, and he has demonstrated no subsequent sinus pauses or syncopes. Regarding the rising awareness of subtle cardiac alterations including autonomic dysfunction and electrocardiogram changes in young patients with PWS and especially the occurrence of unexplained sudden deaths in childhood that may be precipitated by arrhythmia, we suggest that the utility of periodic screening for arrhythmia risk should be evaluated in children with PWS.

Sudden infant death syndrome

Sudden Infant Death Syndrome (SIDS) is a type of sudden and unexpected infant death, a term that encompasses both deaths from SIDS and ultimately all unexpected infant deaths with a determined cause. 1 Between %27 and % 43 of 3500 sudden unexpected infant death cases in the USA annually are due to SIDS. 2, 3 A number of other terms are used in pediatrics to describe sudden and unexpected deaths. Sudden unexpected death of an infant can be used interchangeably with sudden unexpected infant death, and sudden death in youth (VAS) refers to such death in any child 19 years of age or younger. Sudden unexplained early neonatal death is limited to infants who die within the first week of life and is usually congenital. anomaly is caused. Sudden intrauterine unexpected death syndrome refers to stillbirths for which postmortem examination cannot identify a cause, and sudden unexpected death in epilepsy is unexpected death in a person with epilepsy (excluding trauma or suffocation) for which postmortem examination does not reveal an anatomical or toxicological cause.

The role of the icc coordinator within the NHS-SUD pilot project

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Inherited Cardiac Conditions services across the country provide excellent care to families affected by sudden unexpected death, with many Coroners and Pathologists facilitating appropriate referrals and retention of post mortem tissue samples for future genetic testing. However, service provision varies greatly resulting in missed opportunities for tissue retention, signposting to ICC services and disparities in clinical screening. To ensure this gap is closed, the seven NHS Genomic Medicine Service Alliance (GMSA) regions have partnered with the British Heart Foundation to recruit seven ICC coordinators, tasked with coordinating the delivery of a nationally standardised NHS - Coronial Sudden Unexpected Death (SUD) pilot pathway. Methods The ICC coordinator’s main role is to improve the processes and collaboration between the Coronial and their nearest ICC service, increase the number of affected families who are assessed in an NHS ICC service and facilitate genomic counselling and testing at the beginning of the pathway. ICC nurses and genetic counsellors have been recruited into these posts. Their unique skillsets and existing links with pathologists, coroners, coroner officers, families, nurses, geneticists, support groups and cardiologists maximises the deliverables for the duration of the pilot. Results 30 cases of sudden unexplained deaths eligible for entry into the pilot have been signposted and 65 at risk family members have been identified by the seven sites. Some of the most notable results have been facilitation of family referrals, cardiac-genomic counselling, and timely results dissemination. Furthermore, ICC Coordinators have established relationships and delivered training to pathologists, coroner officers and local MDTs, ensuring consistent pathway delivery. Genomic samples are tracked and transferred to the regional genomic laboratory hubs in a standardised manner. Collaboration with external evaluators is ongoing and methods of data capture have been established. Conclusion To ensure national delivery and equitable access to genomic testing, the ICC coordinator role is vital to each ICC service and coronial network. We have highlighted some of the unique skills and relationships needed for a national rollout. Following the outcome of the project evaluation, this role can be expanded to other cardiac nurses and genetic counsellors in other regions.

The fundamental need for unifying phenotypes in sudden unexpected pediatric deaths.

A definitive, authoritative approach to evaluate the causes of unexpected, and ultimately unexplained, pediatric deaths remains elusive, relegating final conclusions to diagnoses of exclusion in the vast majority of cases. Research into unexplained pediatric deaths has focused primarily on sudden infant deaths (under 1 year of age) and led to the identification of several potential, albeit incompletely understood, contributory factors: nonspecific pathology findings, associations with sleep position and environment that may not be uniformly relevant, and the elucidation of a role for serotonin that is practically difficult to estimate in any individual case. Any assessment of progress in this field must also acknowledge the failure of current approaches to substantially decrease mortality rates in decades. Furthermore, potential commonalities with pediatric deaths across a broader age spectrum have not been widely considered. Recent epilepsy-related observations and genetic findings, identified post-mortem in both infants and children who died suddenly and unexpectedly, suggest a role for more intense and specific phenotyping efforts as well as an expanded role for genetic and genomic evaluation. We therefore present a new approach to reframe the phenotype in sudden unexplained deaths in the pediatric age range, collapsing many distinctions based on arbitrary factors (such as age) that have previously guided research in this area, and discuss its implications for the future of postmortem investigation.

Autopsy for Medical Diagnostics: Finding the Cause of Sudden Unexpected Death through Investigation of the Cardiac Conduction System by Serial Sections.

Sudden unexpected death (SUD) is a fatal event that occurs in an apparently healthy subject in a way that such an abrupt outcome could have not been predicted. SUD-including sudden intrauterine unexplained death (SIUD), sudden neonatal unexpected death (SNUD), sudden infant death syndrome (SIDS), sudden unexpected death of the young (SUDY), and sudden unexpected death in the adult (SUDA)-occurs as the first manifestation of an unknown underlying disease or within a few hours of the presentation of a disease. SUD is a major unsolved, shocking form of death that occurs frequently and can happen at any time without warning. For each case of SUD, a review of clinical history data and performance of a complete autopsy, particularly focused on the study of the cardiac conduction system, were carried out according to the necropsy protocol devised by the Lino Rossi Research Center, Università degli Studi di Milano, Italy. Research cases collected and selected for this study were represented by 75 SUD victims that were subdivided into 15 SIUD, 15 SNUD, 15 SUDY, and 15 SUDA victims. After a routine autopsy and clinical history analysis, death remained unexplained, and hence a diagnosis of SUD was assigned to 75 subjects, which included 45 females (60%) and 30 (40%) males ranging in age from 27 gestational weeks to 76 years. Serial sections of the cardiac conduction system disclosed frequent congenital alterations of the cardiac conduction system in fetuses and infants. An age-related significant difference in distribution among the five age-related groups was detected for the following anomalies of the conduction system: central fibrous body (CFB) islands of conduction tissue, fetal dispersion, resorptive degeneration, Mahaim fiber, CFB cartilaginous meta-hyperplasia, His bundle septation, sino-atrial node (SAN) artery fibromuscular thickening, atrio-ventricular junction hypoplasia, intramural right bundle branch, and SAN hypoplasia. The results are useful for understanding the cause of death for all SUD cases that were unexpected and would have otherwise remained unexplained, so as to motivate medical examiners and pathologists to perform more in-depth studies.

Cardiac hereditary diseases: genetic insights from a single center 15-year experience

Abstract Funding Acknowledgements Type of funding sources: None. Background In the last decades, the implementation of high-throughput next-generation (NGS) technologies has profoundly changed the landscape of human genome sequencing. However, the molecular diagnosis in cardiac hereditary diseases is still hampered by the incomplete penetrance, variable expressivity, and genetic heterogeneity of the diseases. Objective We report our 15-year experience on a cohort of consecutive patients (pts) with suspicion of cardiac hereditary disease referred to the specialized cardiogenetic outpatient clinic of our center. Methods We retrospectively reviewed DNA sequencing results of pts referred to our center from July 1st 2007 through December 31st 2021, who were tested with NGS technologies for suspected cardiac hereditary diseases including channelopathies, inherited cardiomyopathies and unexplained sudden cardiac death. Results Among the 488 tested pts, the most frequent clinical indication were presymptomatic screening (37.3%) for a known familial variant, followed by suspected arrhythmic syndrome (28.3%) and hereditary cardiomyopathy (26.8%). A likely pathogenic/pathogenic variant was found in 198 pts for an overall diagnostic yield of 40.6% and of 23.6% considering only index cases. The rate of identified mutation-carriers was higher among pts with cardiomyopathy (45.8%) than among pts with inherited arrhythmic syndromes (37%). Panel A and B display variant distribution in arrhythmic syndromes and cardiomyopathies respectively. In particular, the highest diagnostic yield was observed among pts with suspected hypertrophic cardiomyopathy (60.7%) and catecholaminergic polymorphic ventricular tachycardia (50%), followed by congenital long QT syndrome (48.6%). The pathogenic variants were mainly identified in genes with definitive scientific evidence of causal association with the disease. Conclusions The 15-year experience of our specialized cardiogenetic outpatient clinic has demonstrated the pivotal role of genetic analysis for the diagnostic confirmation and, hence for the therapeutic management of pts with suspected cardiac hereditary disease.

Qualitative assessment of infant sleep practices and other risk factors of sudden infant death syndrome (SIDS) among mothers in Lusaka, Zambia

BackgroundThere is very little information on the beliefs and perceptions of mothers about SIDS and its related risk factors in Africa. To better understand parental decisions about infant sleep practices and other risk factors for SIDS, we conducted focus group discussions (FGDs) with mothers of infants in Lusaka, Zambia.MethodsFGDs involved 35 purposively sampled mothers aged 18–49 years. FGDs were conducted using a semi-structured interview guide in the local language, Nyanja. These were translated, transcribed verbatim into English, and then coded and analyzed using thematic analysis in NVivo 12.ResultsSix FGDs were conducted with 35 mothers in April-May 2021 across two study sites. FGD Participants were generally aware of sudden unexplained infant deaths, with several describing stories of apparent SIDS in the community. The side sleeping position was preferred and perceived to be safer for the infant with most believing the supine position posed an aspiration or choking risk to the infant. Bedsharing was also preferred and perceived to be convenient for breastfeeding and monitoring of the infant. Experienced family members such as grandmothers and mothers-in-law, and health care workers were frequently cited as sources of information on infant sleep position. A heightened awareness of the infant’s sleeping environment was suggested as a mechanism to prevent SIDS and smothering.ConclusionsDecisions about bedsharing and infant sleep position were guided by maternal beliefs and perceptions about what is convenient for breastfeeding and safer for the infant. These concerns are vital to designing tailored interventions to address sleep-related sudden infant losses in Zambia. Public health campaigns with tailored messages that address these concerns are likely to be effective at ensuring optimal uptake of safe sleep recommendations.

Post-mortem genetic testing in sudden cardiac death and genetic screening of relatives at risk: lessons learned from a Czech pilot multidisciplinary study

Sudden cardiac death (SCD) might have an inherited cardiac condition background. Genetic testing supports post-mortem diagnosis and screening of relatives at risk. Our aim is to determine the feasibility of a Czech national collaboration group and to establish the clinical importance of molecular autopsy and family screening. From 2016 to 2021, we have evaluated 100 unrelated SCD cases (71.0% males, age: 33.3 (12.8) years). Genetic testing was performed by next-generation sequencing utilizing a panel of 100 genes related to inherited cardiac/aortic conditions and/or whole exome sequencing. According to autopsy, cases were divided into cardiomyopathies, sudden arrhythmic death syndrome, sudden unexplained death syndrome, and sudden aortic death. We identified pathogenic/likely pathogenic variants following ACMG/AMP recommendations in 22/100 (22.0%) of cases. Since poor DNA quality, we have performed indirect DNA testing in affected relatives or in healthy parents reaching a diagnostic genetic yield of 11/24 (45.8%) and 1/10 (10.0%), respectively. Cardiological and genetic screening disclose 83/301 (27.6%) relatives at risk of SCD. Genetic testing in affected relatives as starting material leads to a high diagnostic yield offering a valuable alternative when suitable material is not available. This is the first multidisciplinary/multicenter molecular autopsy study in the Czech Republic which supports the establishment of this type of diagnostic tests. A central coordinator and proper communication among centers are crucial for the success of a collaboration at a national level.

A novel marker to predict cardiac arrhythmia in epilepsy patients: frontal QRS-T angle.

The most important complication of epilepsy, which is a chronic disorder of the central nervous system, is sudden unexplained death in epilepsy (SUDEP). The causes of SUDEP are complex and multifactorial. Epilepsy patients are at increased risk of cardiovascular events, SUDEP, and ventricular arrhythmias, due to both the disease itself and the effect of antiseizure medications. Previous studies have commonly focused on cardiac repolarization markers in epilepsy patients. This study aimed to investigate frontal QRS-T angle (FTQ angle), a relatively new repolarization parameter, in epilepsy patients. One hundred two epilepsy patients and 86 healthy volunteers as a control group were included in the study. The clinical data of all patients were prospectively recorded during patient visits. All participants underwent 12-lead surface electrocardiography (ECG). SPSS 22 was used to evaluate all data. p<0.05 was considered statistically significant. When the epilepsy patient group and the control group were compared in terms of QRS (89.59±43.63 vs. 80.00±9.82, p=0.050), QT (364.30±36.16 vs. 335.95±35.64, p<0.001), QTc (418.85±27.06 vs. 409.37±26.66, p=0.018) durations, and FTQ angle (46.55±22.06 vs. 20.84±12.70, p<0.001), statistically significant differences were found between the groups. We observed that FTQ angle was significantly higher in individuals exposed to the disease for more than 10 years (39.2±19.0 vs. 54.7±22.5, p<0.001). In addition, according to the multivariate logistic regression analysis, disease duration was an independent predictor of FTQ angle (β=0.263, p=0.009). FTQ angle, a relatively new repolarization parameter, can be used as an inexpensive, easy, reproducible, and reliable ECG marker to predict the risk of adverse cardiac events in epilepsy patients.