Epilepsy is a common neurological disorder associated with increased morbidity and mortality. Sudden unexpected death in epilepsy, also known as SUDEP, is the main cause of death in patients with ...epilepsy. SUDEP has an incidence of 1.2 per 1000 person-years in adults and 0.2 per 1000 person-years in children. SUDEP accounts for 8-17% of deaths in patients with epilepsy. It is commonly associated with a history of generalized tonic-clonic seizures, and its risk may be increased by other factors such as postictal electroencephalographic suppression, prone sleeping position, altered heart rate variability, conduction abnormalities, gender, or antiepileptic medications. Recently, electrocardiograms, electroencephalograms, and imaging markers have helped clinicians stratify SUDEP risk and identify patients in need of close monitoring. However, the pathophysiology of SUDEP is likely multifactorial and still unknown. Improving the knowledge of SUDEP incidence, risk factors, and biomarkers can help design and implement effective prevention strategies.
Inherited cardiovascular diseases are rare diseases that are difficult to diagnose by non-expert professionals. Genetic analyses play a key role in the diagnosis of these diseases, in which the ...identification of a pathogenic genetic variant is often a diagnostic criterion. Therefore, genetic variant classification and routine reinterpretation as data become available represent one of the main challenges associated with genetic analyses. Using the genetic variants identified in an inherited cardiovascular diseases unit during a 10-year period, the objectives of this study were: 1) to evaluate the impact of genetic variant reinterpretation, 2) to compare the reclassification rates between different cohorts of cardiac channelopathies and cardiomyopathies, and 3) to establish the most appropriate periodicity for genetic variant reinterpretation. All the evaluated cohorts (full cohort of inherited cardiovascular diseases, cardiomyopathies, cardiac channelopathies, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, Brugada syndrome, long QT syndrome and catecholaminergic polymorphic ventricular tachycardia) showed reclassification rates above 25%, showing even higher reclassification rates when there is definitive evidence of the association between the gene and the disease in the cardiac channelopathies. Evaluation of genetic variant reclassification rates based on the year of the initial classification showed that the most appropriate frequency for the reinterpretation would be 2 years, with the possibility of a more frequent reinterpretation if deemed convenient. To keep genetic variant classifications up to date, genetic counsellors play a critical role in the reinterpretation process, providing clinical evidence that genetic diagnostic laboratories often do not have at their disposal and communicating changes in classification and the potential implications of these reclassifications to patients and relatives.
Brugada syndrome is a rare inherited arrhythmogenic disease leading to ventricular fibrillation and high risk of sudden death. In 1998, this syndrome was linked with a genetic variant with an ...autosomal dominant pattern of inheritance. To date, rare variants identified in more than 40 genes have been potentially associated with this disease. Variants in regulatory regions, combinations of common variants and other genetic alterations are also proposed as potential origins of Brugada syndrome, suggesting a polygenic or oligogenic inheritance pattern. However, most of these genetic alterations remain of questionable causality; indeed, rare pathogenic variants in the
gene are the only established cause of Brugada syndrome. Comprehensive analysis of all reported genetic alterations identified the origin of disease in no more than 40% of diagnosed cases. Therefore, identifying the cause of this rare arrhythmogenic disease in the many families without a genetic diagnosis is a major current challenge in Brugada syndrome. Additional challenges are interpretation/classification of variants and translation of genetic data into clinical practice. Further studies focused on unraveling the pathophysiological mechanisms underlying the disease are needed. Here we provide an update on the genetic basis of Brugada syndrome.
The left ventricular (LV) ejection fraction (EF) is key to prognosis in dilated cardiomyopathy (DCM). Circulating microRNAs have emerged as reliable biomarkers for heart diseases, included DCM. ...Clinicians need improved tools for greater clarification of DCM EF categorization, to identify high-risk patients. Thus, we investigated whether microRNA profiles can categorize DCM patients based on their EF. 179-differentially expressed circulating microRNAs were screened in two groups: (1) non-idiopathic DCM; (2) idiopathic DCM. Then, 26 microRNAs were identified and validated in the plasma of ischemic-DCM (n = 60), idiopathic-DCM (n = 55) and healthy individuals (n = 44). We identified fourteen microRNAs associated with echocardiographic variables that differentiated idiopathic DCM according to the EF degree. A predictive model of a three-microRNA (miR-130b-3p, miR-150-5p and miR-210-3p) combined with clinical variables (left bundle branch block, left ventricle end-systolic dimension, lower systolic blood pressure and smoking habit) was obtained for idiopathic DCM with a severely reduced-EF. The receiver operating characteristic curve analysis supported the discriminative potential of the diagnosis. Bioinformatics analysis revealed that miR-150-5p and miR-210-3p target genes might interact with each other with a high connectivity degree. In conclusion, our results revealed a three-microRNA signature combined with clinical variables that highly discriminate idiopathic DCM categorization. This is a potential novel prognostic biomarker with high clinical value.
Sudden cardiac death poses a unique challenge to clinicians because it may be the only symptom of an inherited heart condition. Indeed, inherited heart diseases can cause sudden cardiac death in ...older and younger individuals. Two groups of familial diseases are responsible for sudden cardiac death: cardiomyopathies (mainly hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy) and channelopathies (mainly long QT syndrome, Brugada syndrome, short QT syndrome, and catecholaminergic polymorphic ventricular tachycardia). This review focuses on cardiac channelopathies, which are characterized by lethal arrhythmias in the structurally normal heart, incomplete penetrance, and variable expressivity. Arrhythmias in these diseases result from pathogenic variants in genes encoding cardiac ion channels or associated proteins. Due to a lack of gross structural changes in the heart, channelopathies are often considered as potential causes of death in otherwise unexplained forensic autopsies. The asymptomatic nature of channelopathies is cause for concern in family members who may be carrying genetic risk factors, making the identification of these genetic factors of significant clinical importance.
Molecular autopsy in sudden cardiac death Campuzano, Oscar; Sarquella-Brugada, Georgia
Global Cardiology Science & Practice,
01/2023, Letnik:
2023, Številka:
1
Journal Article
Recenzirano
Odprti dostop
A post-mortem genetic analysis in the process of investigating a sudden death episode is known as 'molecular autopsy'. It is usually performed in cases without a conclusive cause of death and after a ...comprehensive medico-legal autopsy. In these sudden unexplained death cases, an underlying inherited arrhythmogenic cardiac disease is the main suspected cause of death. The objective is to unravel a genetic diagnosis of the victim, but it also enables cascade genetic screening of the victim's relatives. Early identification of a deleterious genetic alteration associated with an inherited arrhythmogenic disease may help to adopt preventive personalized measures to reduce risk of malignant arrhythmias and sudden death. It is important to remark that the first symptom of an inherited arrhythmogenic cardiac disease may the malignant arrhythmia and even sudden death. Next-generation sequencing allows a rapid and cost-effectives genetic analysis. Close interaction between the forensic scientist, pathologist, cardiologist, pediatric cardiologist and geneticist has allowed a progressive increase of genetic yield in recent years, identifying the pathogenic genetic alteration. However, large numbers of rare genetic alterations remain classified as having an ambiguous role, impeding a proper genetic interpretation and useful translation into both forensic and cardiological arena.
The use of next-generation sequencing enables a rapid analysis of many genes associated with sudden cardiac death in diseases like Brugada Syndrome. Genetic variation is identified and associated ...with 30-35% of cases of Brugada Syndrome, with nearly 20-25% attributable to variants in SCN5A, meaning many cases remain undiagnosed genetically. To evaluate the role of genetic variants in arrhythmogenic diseases and the utility of next-generation sequencing, we applied this technology to resequence 28 main genes associated with arrhythmogenic disorders.
A cohort of 45 clinically diagnosed Brugada Syndrome patients classified as SCN5A-negative was analyzed using next generation sequencing. Twenty-eight genes were resequenced: AKAP9, ANK2, CACNA1C, CACNB2, CASQ2, CAV3, DSC2, DSG2, DSP, GPD1L, HCN4, JUP, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNJ5, KCNQ1, NOS1AP, PKP2, RYR2, SCN1B, SCN3B, SCN4B, SCN5A, SNTA1, and TMEM43. A total of 85 clinically evaluated relatives were also genetically analyzed to ascertain familial segregation.
Twenty-two patients carried 30 rare genetic variants in 12 genes, only 4 of which were previously associated with Brugada Syndrome. Neither insertion/deletion nor copy number variation were detected. We identified genetic variants in novel candidate genes potentially associated to Brugada Syndrome. These include: 4 genetic variations in AKAP9 including a de novo genetic variation in 3 positive cases; 5 genetic variations in ANK2 detected in 4 cases; variations in KCNJ2 together with CASQ2 in 1 case; genetic variations in RYR2, including a de novo genetic variation and desmosomal proteins encoding genes including DSG2, DSP and JUP, detected in 3 of the cases. Larger gene panels or whole exome sequencing should be considered to identify novel genes associated to Brugada Syndrome. However, application of approaches such as whole exome sequencing would difficult the interpretation for clinical purposes due to the large amount of data generated. The identification of these genetic variants opens new perspectives on the implications of genetic background in the arrhythmogenic substrate for research purposes.
As a paradigm for other arrhythmogenic diseases and for unexplained sudden death, our data show that clinical genetic diagnosis is justified in a family perspective for confirmation of genetic causality. In the era of personalized medicine using high-throughput tools, clinical decision-making is increasingly complex.
Dilated cardiomyopathy, a major cause of chronic heart failure and cardiac transplantation, is characterized by left ventricular or biventricular heart dilatation. In nearly 50% of cases the ...pathology is inherited, and more than 60 genes have been reported as disease-causing. However, in 30% of familial cases the mutation remains unidentified even after comprehensive genetic analysis. This study clinically and genetically assessed a large Spanish family affected by dilated cardiomyopathy to search for novel variations.
Our study included a total of 100 family members. Clinical assessment was performed in alive, and genetic analysis was also performed in alive and 1 deceased relative. Genetic screening included resequencing of 55 genes associated with sudden cardiac death, and Sanger sequencing of main disease-associated genes. Genetic analysis identified a frame-shift variation in BAG3 (p.H243Tfr*64) in 32 patients. Genotype-phenotype correlation identified substantial heterogeneity in disease expression. Of 32 genetic carriers (one deceased), 21 relatives were clinically affected, and 10 were asymptomatic. Seventeen of the symptomatic genetic carriers exhibited proto-diastolic septal knock by echocardiographic assessment.
We report p.H243Tfr*64_BAG3 as a novel pathogenic variation responsible for familial dilated cardiomyopathy. This variation correlates with a more severe phenotype of the disease, mainly in younger individuals. Genetic analysis in families, even asymptomatic individuals, enables early identification of individuals at risk and allows implementation of preventive measures.
Sudden unexplained death may be the first manifestation of an unknown inherited cardiac disease. Current genetic technologies may enable the unraveling of an etiology and the identification of ...relatives at risk. The aim of our study was to define the etiology of natural deaths, younger than 50 years of age, and to investigate whether genetic defects associated with cardiac diseases could provide a potential etiology for the unexplained cases.
Our cohort included a total of 789 consecutive cases (77.19% males) <50 years old (average 38.6±12.2 years old) who died suddenly from non-violent causes. A comprehensive autopsy was performed according to current forensic guidelines. During autopsy a cause of death was identified in most cases (81.1%), mainly due to cardiac alterations (56.87%). In unexplained cases, genetic analysis of the main genes associated with sudden cardiac death was performed using Next Generation Sequencing technology. Genetic analysis was performed in suspected inherited diseases (cardiomyopathy) and in unexplained death, with identification of potentially pathogenic variants in nearly 50% and 40% of samples, respectively.
Cardiac disease is the most important cause of sudden death, especially after the age of 40. Close to 10% of cases may remain unexplained after a complete autopsy investigation. Molecular autopsy may provide an explanation for a significant part of these unexplained cases. Identification of genetic variations enables genetic counseling and undertaking of preventive measures in relatives at risk.
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