Pediatric Left Posteroseptal Accessory Pathway Ablation from Giant Coronary Sinus with Persistent Left Superior Cava

We report a pediatric patient with persistent left superior vena cava and a D-transposition of great arteries, which is an uncommon relation. It is crucial to know the anatomy of the persistent left superior vena cava and the dilated coronary sinus to plan the mapping techniques in cases of posterior accessory pathways

Negative Autopsy in Infant and Juvenile Population: Role of Cardiac Arrhythmias

Negative autopsy is a post-mortem examination in which a comprehensive analysis does not provide a cause of death. These include situation of death, anatomical and histological analysis, toxicology and microbiological study. A low part of autopsies remain without a conclusive cause of death, but all these cases are usually seen in young population, apparently healthy who died suddenly and unexpectedly. In these situations a cardiac arrhythmia is suspected as cause of death and genetic testing is recommended despite not regularly performed. Sudden death is a natural and unexpected decease that occurs in apparently healthy people, or whose disease was not severe enough to expect a fatal outcome. It can be due to several pathologies, usually of cardiac cause and called sudden cardiac death. In infants and young people, both long QT syndrome and catecholaminergic polymorphic ventricular tachycardia are main causes in negative autopsies. These genetic diseases lead to ventricular fibrillation, syncope and sudden cardiac death in a normal heart. Unfortunately, sudden cardiac death could be the first manifestation of the diseases, being early identification and prevention a crucial point in current medical practice. This chapter focuses on sudden death and negative autopsy in young population, mainly due to cardiac arrhythmias

Recent Advances in Short QT Syndrome

Short QT syndrome is a highly malignant inherited cardiac disease characterized by ventricular tachyarrhythmias leading to syncope and sudden cardiac death. It is responsible of lethal episodes in young people, mainly infants. International guidelines establish diagnostic criteria with the presence of a QTc ≤ 340 ms in the electrocardiogram despite clinical diagnostic values remain controversial. In last years, clinical diagnosis, risk stratification as well as preventive therapies have been improved due to identification of pathophysiological mechanisms. The only effective option is implantation of a defibrillator despite Quinidine may be at times an effective option. Currently, a limited number of rare variants have been identified in seven genes, which account for nearly 20–30% of families. However, some of these variants are associated with phenotypes showing a shorter QT interval but no conclusive diagnosis of Short QT syndrome. Therefore, an exhaustive interpretation of each variant and a close genotype-phenotype correlation is necessary before clinical translation. Here, we review the main clinical and genetic hallmarks of this rare entity

Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population

Sudden death is a rare event in the pediatric population but with a social shock due to its presentation as the first symptom in previously healthy children. Comprehensive autopsy in pediatric cases identify an inconclusive cause in 40-50% of cases. In such cases, a diagnosis of sudden arrhythmic death syndrome is suggested as the main potential cause of death. Molecular autopsy identifies nearly 30% of cases under 16 years of age carrying a pathogenic/potentially pathogenic alteration in genes associated with any inherited arrhythmogenic disease. In the last few years, despite the increasing rate of post-mortem genetic diagnosis, many families still remain without a conclusive genetic cause of the unexpected death. Current challenges in genetic diagnosis are the establishment of a correct genotype-phenotype association between genes and inherited arrhythmogenic disease, as well as the classification of variants of uncertain significance. In this review, we provide an update on the state of the art in the genetic diagnosis of inherited arrhythmogenic disease in the pediatric population. We focus on emerging publications on gene curation for genotype-phenotype associations, cases of genetic overlap and advances in the classification of variants of uncertain significance. Our goal is to facilitate the translation of genetic diagnosis to the clinical area, helping risk stratification, treatment and the genetic counselling of families

Clinical interpretation of genetic variants in arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy is an inherited cardiac entity characterized by right ventricular, or biventricular, fibrofatty replacement of myocardium. Structural alterations may lead to sudden cardiac death, mainly in young males during exercise. Autosomal dominant pattern of inheritance is reported in most parts of pathogenic genetic variations identified. Currently, 13 genes have been associated with the disease but nearly 40 % of clinically diagnosed cases remain without a genetic diagnosis. New genetic technologies allow further genetic analysis, generating a significant amount of genetic data in novel genes, which is often classified as of ambiguous significance. We focus on genetic advances of arrhythmogenic right ventricular cardiomyopathy, helping clinicians to interpret and translate genetic data into clinical practice

Brugada Syndrome in Women: What Do We Know After 30 Years?

Brugada syndrome (BrS) was initially described in 1992 by Josep and Pedro Brugada as an arrhythmogenic disease characterized by ST segment elevation in the right precordial leads and increased risk of sudden cardiac death (SCD). Alterations in the SCN5A gene are responsible for approximately 30% of cases of BrS, following an autosomal dominant pattern of inheritance. However, despite its autosomal transmission, sex-related differences are widely accepted. BrS is more prevalent in males than in females (8-10 times), with males having a 5.5-fold higher risk of SCD. There are also differences in clinical presentation, with females being more frequently asymptomatic and older than males at the time of diagnosis. Some factors have been identified that could explain these differences, among which testosterone seems to play an important role. However, only 30% of the available publications on the syndrome include sex-related information. Therefore, current findings on BrS are based on studies conducted mainly in male population, despite the wide acceptance of gender differences. The inclusion of complete clinical and demographic information in future publications would allow a better understanding of the phenotypic variability of BrS in different age and sex groups helping to improve the diagnosis, management and risk management of SCD.Copyright © 2022 Martínez-Barrios, Arbelo, Cesar, Cruzalegui, Fiol, Díez-Escuté, Hernández, Brugada, Brugada, Campuzano and Sarquella-Brugada

Update on Genes Associated with Arrhythmogenic Cardiomyopathy

Arrhythmogenic cardiomyopathy is a rare genetic entity characterized by progressive fibro-fatty replacement of myocardium leading to malignant arrhythmias, syncope, and sudden cardiac death. Mostly it affects the right ventricle, but cases have also been described with biventricular and even isolated left ventricular involvement. The disease affects mainly young males and arrhythmias are usually induced by exercise. Arrhythmogenic cardiomyopathy has a genetic origin and is basically caused by deleterious alterations in genes encoding desmosomal proteins, especially plakophilin-2. To date, more than 400 rare genetic alterations have been identified in 18 genes, mainly with autosomal dominant inheritance, but some recessive forms have also been reported (Naxos disease and Carvajal syndrome). A comprehensive genetic analysis identifies a rare variant as potential cause of the disease in around 60% of patients, suggesting the existence of unknown genes as well as other genome alterations not yet discovered. Genetic interpretation classifies some of these rare variants as ambiguous, playing an uncertain role in arrhythmogenic cardiomyopathy. This makes a proper translation of genetic data into clinical practice difficult. Moreover, incomplete penetrance and variable phenotypic expression makes it difficult to arrive at the correct diagnosis. In the present chapter, we focus on recent advances in the knowledge regarding the genetic basis of arrhythmogenic cardiomyopathy

Personalized Genetic Diagnosis of Congenital Heart Defects in Newborns

Congenital heart disease is a group of pathologies characterized by structural malformations of the heart or great vessels. These alterations occur during the embryonic period and are the most frequently observed severe congenital malformations, the main cause of neonatal mortality due to malformation, and the second most frequent congenital malformations overall after malformations of the central nervous system. The severity of different types of congenital heart disease varies depending on the combination of associated anatomical defects. The causes of these malformations are usually considered multifactorial, but genetic variants play a key role. Currently, use of high-throughput genetic technologies allows identification of pathogenic aneuploidies, deletions/duplications of large segments, as well as rare single nucleotide variants. The high incidence of congenital heart disease as well as the associated complications makes it necessary to establish a diagnosis as early as possible to adopt the most appropriate measures in a personalized approach. In this review, we provide an exhaustive update of the genetic bases of the most frequent congenital heart diseases as well as other syndromes associated with congenital heart defects, and how genetic data can be translated to clinical practice in a personalized approach.This work was supported by Obra Social "La Caixa Foundation" (LCF/PR/GN16/50290001, and LCF/PR/GN19/50320002). Funders had no role in study design, data collection, data analysis, interpretation, or writing of the report

Molecular autopsy in sudden cardiac death

Actualmente hay un porcentaje importante de autopsias que quedan sin un diagnóstico concluyente del fallecimiento, especialmente cuando este evento letal se produce súbitamente. El análisis genético se ha ido incorporando recientemente al campo de la medicina forense, sobre todo en aquellos pacientes que han fallecido de forma repentina, y donde no se identifica causa concluyente del fallecimiento tras una autopsia médico-legal completa. En estos casos las enfermedades eléctricas primarias son las principales responsables del fallecimiento. Hasta la fecha se han descrito más de 40 genes asociados a afecciones arritmogénicas causantes de muerte súbita cardiaca. Las principales enfermedades arritmogénicas son el síndrome de QT largo y la taquicardia ventricular; estudios genéticos post-mortem no solo permiten llevar a cabo un diagnóstico de la causa del fallecimiento, sino que también permiten una traslación clínica hacia los familiares, focalizado en la identificación precoz de individuos en riesgo de síncope, así como adopción de medidas terapéuticas personalizadas para la prevención de un episodio arrítmico letal.Currently, there are a significant percentage of autopsies left without a conclusive diagnosis of death, especially when this lethal event occurs suddenly. Genetic analysis has been recently incorporated into the field of forensic medicine, especially in patients with sudden death and where no conclusive cause of death is identified after a complete medicallegal autopsy. Inherited arrhythmogenic diseases are the main cause of death in these cases. To date, more than 40 genes have been associated with arrhythmogenic disease, and causing sudden cardiac death has been described. The main arrhythmogenic diseases are Long QT Syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia, Brugada Syndrome, and Short QT Syndrome. These post-mortem genetic studies, not only allow a diagnosis of the cause of death, but also allow a clinical translation in relatives, focusing on the early identification of individuals at risk of syncope, as well as adopting personalised therapeutic measures for the prevention of a lethal arrhythmic episode

Generation of four induced pluripotent stem cell lines from a family harboring a single nucleotide variant in SCN5A

Patient-derived induced pluripotent stem cells (iPSC) are a valuable approach to model cardiovascular diseases. We nucleofected non-integrating episomal vectors in skin fibroblasts of three family members carrying a single nucleotide variant (SNV) in SCN5A, which encodes the cardiac-type sodium channel, and of a related healthy control. The SNV SCN5A_c.4573G > A had been previously identified in a Brugada Syndrome patient. The resulting iPS cell lines differentiate into cells of the 3 germ layers, display normal karyotypes and express pluripotency surface markers and genes. Thus, they are a reliable source to study the effect of the identified mutation in a physiologically relevant environment