Search

Background Although genetic variants in MYH7 are the most frequent cause of pediatric genetic dilated cardiomyopathy (DCM), there are no studies available describing this entity. We sought to describe clinical features, analyze variant location, and explore predictors of bad prognosis in pediatric MYH7‐related DCM. Methods and Results We evaluated clinical records from 44 patients (24 men; median age at diagnosis, 0.54 [interquartile range, 0.01–10.8] years) with pathogenic/likely pathogenic variants in MYH7 diagnosed with DCM at pediatric age (

Background/Objectives: Inherited arrhythmogenic syndromes comprise a heterogenic group of genetic entities that lead to malignant arrhythmias and sudden cardiac death. Genetic testing has become crucial to understand the disease etiology and allow for the early identification of relatives at risk; however, it requires an accurate interpretation of the data to achieve a clinically actionable outcome. This is particularly challenging for the large number of rare variants obtained by current high-throughput techniques, which are mostly classified as of unknown significance. Methods: In this work, we present a new algorithm for the genetic interpretation of the remaining rare variants in order to shed light on their potential clinical implications and reduce the burden of unknown significance. Results: Our study illustrates the potential utility of our individualized comprehensive stepwise analyses focused on the rare variants associated with IAS, which are currently classified as ambiguous, to further determine their trends towards pathogenicity or benign traits. Conclusions: We advocate for personalized disease-focused population frequency data and family segregation analyses for all rare variants that remain ambiguous to further clarify their role. The current ambiguity should not influence medical decisions, but a potential deleterious role would suggest a closer clinical follow-up and frequent genetic data review for a more personalized clinical approach.

Sudden cardiac death is a rare but socially devastating event, especially if occurs in young people. Usually, this unexpected lethal event occurs during or just after exercise. One of the leading causes of sudden cardiac death is inherited arrhythmogenic syndromes, a group of genetic entities characterised by incomplete penetrance and variable expressivity. Exercise can be the trigger for malignant arrhythmias and even syncope in population with a genetic predisposition, being sudden cardiac death as the first symptom. Due to genetic origin, family members must be clinically assessed and genetically analysed after diagnosis or suspected diagnosis of a cardiac channelopathy. Early identification and adoption of personalised preventive measures is crucial to reduce risk of arrhythmias and avoid new lethal episodes. Despite exercise being recommended by the global population due to its beneficial effects on health, particular recommendations for these patients should be adopted considering the sport practised, level of demand, age, gender, arrhythmogenic syndrome diagnosed but also genetic diagnosis. Our review focuses on the role of genetic background in sudden cardiac death during exercise in child and young population.

Arrhythmogenic cardiomyopathy is an inherited entity characterized by irregular cell–cell adhesion, cardiomyocyte death and fibro-fatty replacement of ventricular myocytes, leading to malignant ventricular arrythmias, contractile dysfunction and sudden cardiac death. Pathogenic variants in genes that encode desmosome are the predominant cause of arrhythmogenic cardiomyopathy. Moreover, signalling pathways such as Wnt/ß-catenin and transforming growth factor-β have been involved in the disease progression. However, still little is known about the molecular pathophysiological mechanisms that underlie arrhythmogenic cardiomyopathy pathogenesis. We used mRNA and small RNA sequencing to analyse the transcriptome of health and arrhythmogenic cardiomyopathy of autopsied human hearts. Our results showed 697 differentially expressed genes and eight differentially expressed miRNAs. Functional enrichment revealed mitochondrial respiratory-related pathways, impaired response to oxidative stress, apoptotic signalling pathways and inflammatory response-related and extracellular matrix response pathways. Furthermore, analysis of the miRNA–mRNA interactome identified eleven negatively correlated miRNA-target pairs for arrhythmogenic cardiomyopathy. Our finding revealed novel arrhythmogenic cardiomyopathy-related miRNAs with important regulatory function in disease pathogenesis, highlighting their value as potential key targets for therapeutic approaches.

Los síndromes arritmogénicos hereditarios son un grupo de patologías cardiacas asociadas a arritmias malignas y un mayor riesgo de muerte súbita cardiaca, en ocasiones la primera manifestación de la patología. Estos síndromes suelen presentarse especialmente en población menor de 35 años, a menudo causando episodios arritmogénicos durante la práctica deportiva. Por esta razón, resulta esencial realizar estudios cardiológicos exhaustivos a deportistas, independientemente del deporte practicado, nivel de exigencia, edad o sexo para la prevención de estos episodios. Las principales entidades incluidas en este grupo son el síndrome de QT largo, el síndrome de Brugada, el síndrome de QT corto y la Taquicardia Ventricular Polimórfica Catecolaminérgica. La comprensión de los mecanismos que predisponen a las arritmias cardiacas hereditarias sigue siendo uno de los retos a resolver por la investigación biomédica ya que algunas de las complicaciones en las arritmias sólo se presentan cuando existe una interacción perfecta entre factores ambientales y genéticos. Los avances en el estudio del genoma humano han permitido identificar multitud de variantes en diversos genes asociados a este tipo de síndromes cardiacos. Al ser síndromes hereditarios, otros miembros de la familia pueden ser portadores del mismo defecto genético por lo que realizar un estudio fenotipo-genotipo en estas familias permite identificar otros miembros a riesgo de padecer episodios arritmogénicos letales. Palabras claves: Genética. Deporte. Muerte súbita cardíaca. Síndromes arrítmicos hereditarios. Abstract. Inherited arrhythmogenic syndromes are a group of cardiac pathologies associated with malignant arrhythmias and sudden cardiac death, sometimes the first manifestation of the pathology. These syndromes usually manifest in the population under 35 years of age, causing arrhythmogenic episodes during sports practice. For this reason, carrying out exhaustive cardiological studies on athletes, regardless of the sport practiced, level of demand, age or gender, is essential to prevent these malignant episodes. The main entities included in this group are Long QT syndrome, Brugada syndrome, Short QT syndrome and Catecholaminergic Polymorphic Ventricular Tachycardia. A large part of the mechanisms that predispose to inherited cardiac arrhythmias continue to be one of the challenges to be resolved by biomedical research, since some of the complications in arrhythmias only occur when there is a perfect interaction between environmental and genetic factors. Advances in the study of the genome have made it possible to identify a multitude of variants in numerous genes, being these genetic alterations responsible for the predisposition to arrhythmias. As these are hereditary syndromes, other family members may be carriers of the same genetic defect, so carrying out a phenotype-genotype correlation in these families makes it possible to identify other members at risk of suffering lethal arrhythmogenic episodes. Key Words: Genetics. Sport. Sudden cardiac death. Inherited arrhythmic syndromes.

Inherited arrhythmogenic syndromes (IASs) are a heterogeneous group of rare cardiac entities of genetic origin [...]

Long QT Syndrome (LQTS) is a rare, inherited channelopathy characterized by cardiac repolarization dysfunction, leading to a prolonged rate-corrected QT interval in patients who are at risk for malignant ventricular tachyarrhythmias, syncope, and even sudden cardiac death. A complex genetic origin, variable expressivity as well as incomplete penetrance make the diagnosis a clinical challenge. In the last 10 years, there has been a continuous improvement in diagnostic and personalized treatment options. Therefore, several factors such as sex, age diagnosis, QTc interval, and genetic background may contribute to risk stratification of patients, but it still currently remains as a main challenge in LQTS. It is widely accepted that sex is a risk factor itself for some arrhythmias. Female sex has been suggested as a risk factor in the development of malignant arrhythmias associated with LQTS. The existing differences between the sexes are only manifested after puberty, being the hormones the main inducers of arrhythmias. Despite the increased risk in females, no more than 10% of the available publications on LQTS include sex-related data concerning the risk of malignant arrhythmias in females. Therein, the relevance of our review data update concerning women and LQTS.

Introduction: LMNA-related muscular dystrophy is a rare entity that produce “laminopathies” such as Emery–Dreifuss muscular dystrophy (EDMD), limb–girdle muscular dystrophy type 1B (LGMD1B), and LMNA-related congenital muscular dystrophy (L-CMD). Heart failure, malignant arrhythmias, and sudden death may occur. No consensus exists on cardiovascular management in pediatric laminopathies. The aim was to perform an exhaustive cardiologic follow-up in pediatric patients diagnosed with LMNA-related muscular dystrophy.Methods: Baseline cardiac work-up consisted of clinical assessment, transthoracic Doppler echocardiography, 12-lead electrocardiogram, electrophysiological study, and implantation of a long-term implantable cardiac loop recorder (ILR).Results: We enrolled twenty-eight pediatric patients diagnosed with EDMD (13 patients), L-CMD (11 patients), LGMD1B (2 patients), and LMNA-related mild weakness (2 patients). Follow-up showed dilated cardiomyopathy (DCM) in six patients and malignant arrhythmias in five (four concomitant with DCM) detected by the ILR that required implantable cardioverter defibrillator (ICD) implantation. Malignant arrhythmias were detected in 20% of our cohort and early-onset EDMD showed worse cardiac prognosis.Discussion: Patients diagnosed with early-onset EDMD are at higher risk of DCM, while potentially life-threatening arrhythmias without DCM appear earlier in L-CMD patients. Early onset neurologic symptoms could be related with worse cardiac prognosis. Specific clinical guidelines for children are needed to prevent sudden death.

Background: Laminopathies are caused by rare alterations in LMNA, leading to a wide clinical spectrum. Though muscular dystrophy begins at early ages, disease progression is different in each patient. We investigated variability in laminopathy phenotypes by performing a targeted genetic analysis of patients diagnosed with LMNA-related muscular dystrophy to identify rare variants in alternative genes, thereby explaining phenotypic differences.Methods: We analyzed 105 genes associated with muscular diseases by targeted sequencing in 26 pediatric patients of different countries, diagnosed with any LMNA-related muscular dystrophy. Family members were also clinically assessed and genetically analyzed.Results: All patients carried a pathogenic rare variant in LMNA. Clinical diagnoses included Emery-Dreifuss muscular dystrophy (EDMD, 13 patients), LMNA-related congenital muscular dystrophy (L-CMD, 11 patients), and limb-girdle muscular dystrophy 1B (LGMD1B, 2 patients). In 9 patients, 10 additional rare genetic variants were identified in 8 genes other than LMNA. Genotype-phenotype correlation showed additional deleterious rare variants in five of the nine patients (3 L-CMD and 2 EDMD) with severe phenotypes.Conclusion: Analysis f known genes related to muscular diseases in close correlation with personalized clinical assessments may help identify additional rare variants of LMNA potentially associated with early onset or most severe disease progression.

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.

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.

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.

Introduction: Long QT syndrome is the main arrhythmogenic disease responsible for sudden death in infants, especially in the first days of life. Performing an electrocardiogram in newborns could enable early diagnosis and adoption of therapeutic measures focused on preventing lethal arrhythmogenic events. However, the inclusion of an electrocardiogram in neonatal screening protocols still remains a matter of discussion. To comprehensively analyse the potential clinical value of performing an electrocardiogram and subsequent follow-up in a cohort of newborns.Methods: Electrocardiograms were performed in 685 neonates within the first week of life. One year follow-up was performed if QTc > 450 ms identified. Comprehensive genetic analysis using massive sequencing was performed in all cases with QTc > 470 ms.Results: We identified 54 neonates with QTc > 450 ms/ 480 ms at birth and, if persistent, pharmacological treatment was administrated during follow-up. A rare variant was identified as the potential cause of long QT syndrome in five cases. Three cases showed a family history of sudden arrhythmogenic death.Conclusions: Our prospective study identifies 0.14% of cases with a definite long QT, supporting implementation of electrocardiograms in routine pediatric protocols. It is an effective, simple and non-invasive approach that can help prevent sudden death in neonates and their relatives. Genetic analyses help to unravel the cause of arrhythmogenic disease in diagnosing neonates. Further, clinical assessment and genetic analysis of relatives allowed early identification of family members at risk of arrhythmias helping to adopt preventive personalized measures.

Aim: To perform a comprehensive phenotype-genotype correlation of all rare variants in Triadin leading to malignant arrhythmias in pediatrics.Methods: Triadin knockout syndrome is a rare entity reported in pediatric population. This syndrome is caused by rare variants in the TRDN gene. Malignant ventricular arrhythmias and sudden cardiac death can be a primary manifestation of disease. Although pharmacological measures are effective, some patients require an implantable defibrillator due to high risk of arrhythmogenic episodes.Main Results: Fourteen rare genetic alterations in TRDN have been reported to date. All of these potentially pathogenic alterations are located in a specific area of TRDN, highlighting this hot spot as an arrhythmogenic gene region.Conclusions: Early recognition and comprehensive interpretation of alterations in Triadin are crucial to adopt preventive measures and avoid malignant arrhythmogenic episodes in pediatric population.

La pandemia de COVID-19 ha infligido grandes estragos a la población y en especial al personal de salud. Los esfuerzos de reanimación exigen modificaciones potenciales de las guías internacionales existentes de reanimación cardiopulmonar (RCP) debido al elevado índice de contagiosidad del virus SARS-CoV-2. Se considera que hasta 15% de los casos de COVID-19 tiene una enfermedad grave y 5% padece un trastorno crítico con una mortalidad promedio del 3%, la cual varía según sean el país y las características de los pacientes. La edad y las comorbilidades como la hipertensión arterial, enfermedad cardiovascular, obesidad y diabetes incrementan la mortalidad hasta 24%. También se ha informado un aumento reciente del número de casos de paro cardíaco extrahospitalario (PCEH). Aunque el paro cardíaco (PC) puede ser efecto de factores diversos en estos pacientes, en la mayoría de los casos se ha demostrado que el origen es respiratorio, con muy pocos casos de causa cardíaca. Se debe considerar la indicación de iniciar o continuar las maniobras de RCP por dos razones fundamentales: la posibilidad de sobrevida de las víctimas, que hasta la fecha se ha registrado muy baja, y el riesgo de contagiar al personal de salud, que es muy alto.

Background During the severe acute respiratory syndrome Coronavirus 2 pandemic, there has been an increase in hyperinflammatory presentation in previously healthy children with a variety of cardiac manifestations. Our objective is to describe the cardiac manifestations found in an international cohort of 55 pediatric cases with multi‐system inflammatory syndrome during the severe acute respiratory syndrome Coronavirus 2 pandemic. Methods and Results We reviewed data on previously healthy pediatric patients (≤18 years) with structurally normal hearts who presented at hospitals in the United States, United Kingdom, Spain, and Pakistan with multi‐system inflammatory syndrome in children and had consultation with a pediatric cardiologist. Data collected included demographics, clinical presentation, laboratory values, electrocardiographic abnormalities, echocardiographic findings, and initial therapies. A total of 55 patients presented with multi‐system inflammatory syndrome in children. Thirty‐five patients (64%) had evidence of decreased left ventricular function, 17 (31%) had valvulitis, 12 (22%) with pericardial effusion, and 11 (20%) with coronary abnormalities. Twenty‐seven (49%) required intensive care unit admission and 24 (44%) had evidence of shock. Eleven patients (20%) fulfilled complete Kawasaki disease criteria and had lower NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), D‐dimer, and ferritin levels compared with those who did not fulfill criteria. Electrophysiologic abnormalities occurred in 6 patients and included complete atrioventricular block, transient atrioventricular block, and ventricular tachycardia. Conclusions To our knowledge, we describe the first international cohort of pediatric patients with multi‐system inflammatory syndrome in children during the severe acute respiratory syndrome Coronavirus 2 pandemic with a range of cardiac manifestations. This article brings awareness and alertness to the global medical community to recognize these children during the pandemic and understand the need for early cardiology evaluation and follow‐up.

ABSTRACT: Background: Accurate interpretation of rare genetic variants is a challenge for clinical translation. Updates in recommendations for rare variant classification require the reanalysis and reclassification. We aim to perform an exhaustive re-analysis of rare variants associated with inherited arrhythmogenic syndromes, which were classified ten years ago, to determine whether their classification aligns with current standards and research findings. Methods: In 2010, the rare variants identified through genetic analysis were classified following recommendations available at that time. Nowadays, the same variants have been reclassified following current American College of Medical Genetics and Genomics recommendations. Findings: Our cohort included 104 cases diagnosed with inherited arrhythmogenic syndromes and 17 post-mortem cases in which inherited arrhythmogenic syndromes was cause of death. 71.87% of variants change their classification. While 65.62% of variants were classified as likely pathogenic in 2010, after reanalysis, only 17.96% remain as likely pathogenic. In 2010, 18.75% of variants were classified as uncertain role but nowadays 60.15% of variants are classified of unknown significance. Interpretation: Reclassification occurred in more than 70% of rare variants associated with inherited arrhythmogenic syndromes. Our results support the periodical reclassification and personalized clinical translation of rare variants to improve diagnosis and adjust treatment. Funding: Obra Social ''La Caixa Foundation'' (ID 100010434, LCF/PR/GN16/50290001 and LCF/PR/GN19/50320002), Fondo Investigacion Sanitaria (FIS PI16/01203 and FIS, PI17/01690), Sociedad Española de Cardiología, and “Fundacio Privada Daniel Bravo Andreu”. Keywords: Sudden cardiac death, Arrhythmias, Pathogenicity, Genetics

Introduction: Approved drugs for attention deficit hyperactivity disorder (ADHD) in Spain are methylphenidate, lisdexamphetamine, atomoxetine and guanfacine. Due to adverse cardiovascular effects, mainly increased blood pressure and heart rate, its use in patients with known or undiagnosed heart disease may be controversial. Objective: To obtain a consensus document from the Spanish Society of Paediatric Cardiology and Congenital Heart Diseases (SECPCC) and experts from other Agencies and Societies as a guide for the paediatric cardiologist and physicians who treat children and adolescents with ADHD. Method: An analysis was performed on the bibliography and Clinical Practice Guidelines, technical data sheets approved by the Spanish Agency of Medicines and Health Devices, and the Spanish Ministry of Health Guidelines. A Working Group was formed, with a Coordinator, as well as members of the Clinical Cardiology Working Group and Arrhythmia Group of the SECPCC. This Group produced a preliminary document that was reviewed by a group of external experts (List 1) and a group of internal experts of the SECPCC (List 2) with a consensus being reached on the final document. Results: The recommendations of the SECPCC and the group of experts are presented on cardiovascular evaluation prior to treatment in children and adolescents with unknown cardiovascular disease and with known cardiovascular disease.The recommendations of the SECPCC and the group of experts are also presented on the use of medications for ADHD in children and adolescents with cardiological symptoms with no evidence of heart disease, congenital heart disease, cardiomyopathy, Marfan syndrome and other aortic diseases, hypertension, and arrhythmias. Resumen: Introducción: Los fármacos aprobados para el trastorno por déficit de atención con hiperactividad (TDAH) en España son: metilfenidato, lisdexanfetamina, atomoxetina y guanfacina. Debido a los efectos adversos cardiovasculares que pueden producir, principalmente aumento de la tensión arterial y la frecuencia cardiaca, su uso en pacientes con cardiopatías conocidas o no diagnosticadas puede ser controvertido. Objetivo: Realización de un documento de consenso de la Sociedad Española de Cardiología Pediátrica y Cardiopatías Congénitas (SECPCC) y expertos de otras Agencias y Sociedades como instrumento para el cardiólogo infantil y los médicos que tratan niños y adolescentes con TDAH. Metodología: Análisis de la bibliografía y Guías de Práctica Clínica, fichas técnicas aprobadas por la Agencia Española del Medicamento y Productos Sanitarios y Guía del Ministerio de Sanidad español. Formación de un Grupo de trabajo con un Coordinador, miembros de los grupos de trabajo de Cardiología Clínica y Arritmias de la SECPCC. Este Grupo realizó un documento que fue revisado por un grupo de expertos externos (Anexo 1) y un grupo de expertos internos de la SECPCC (Anexo 2) llegando a un consenso para la obtención del documento final. Resultados: Se presentan las recomendaciones de la SECPCC y el grupo de expertos sobre la evaluación cardiovascular previa al tratamiento en niños y adolescentes sin enfermedad cardiovascular conocida y con enfermedad cardiovascular conocida. Se presentan las recomendaciones de la SECPCC y el grupo de expertos sobre el uso de medicamentos para el TDAH en niños y adolescentes con síntomas cardiológicos sin evidencia de cardiopatía, cardiopatías congénitas, miocardiopatías, síndrome de Marfan y otras aortopatías, hipertensión arterial y arritmias.

Resumen: Introducción: Los fármacos aprobados para el trastorno por déficit de atención con hiperactividad (TDAH) en España son: metilfenidato, lisdexanfetamina, atomoxetina y guanfacina. Debido a los efectos adversos cardiovasculares que pueden producir, principalmente aumento de la presión arterial y la frecuencia cardíaca, su uso en pacientes con cardiopatías conocidas o no diagnosticadas puede ser controvertido. Objetivo: Realización de un documento de consenso de la Sociedad Española de Cardiología Pediátrica y Cardiopatías Congénitas (SECPCC) y expertos de otras agencias y sociedades como instrumento para el cardiólogo infantil y los médicos que tratan niños y adolescentes con TDAH. Metodología: Análisis de la bibliografía y las guías de práctica clínica, fichas técnicas aprobadas por la Agencia Española del Medicamento y Productos Sanitarios y Guía del Ministerio de Sanidad español. Formación de un grupo de trabajo con un coordinador, miembros de los grupos de trabajo de Cardiología Clínica y Arritmias de la SECPCC. Este grupo realizó un documento que fue revisado por un grupo de expertos externos y un grupo de expertos internos de la SECPCC, llegando a un consenso para la obtención del documento final. Resultados: Se presentan las recomendaciones de la SECPCC y el grupo de expertos sobre la evaluación cardiovascular previa al tratamiento en niños y adolescentes sin enfermedad cardiovascular conocida y con enfermedad cardiovascular conocida. Se presentan las recomendaciones de la SECPCC y el grupo de expertos sobre el uso de medicamentos para el TDAH en niños y adolescentes con síntomas cardiológicos sin evidencia de cardiopatía, cardiopatías congénitas, miocardiopatías, síndrome de Marfan y otras aortopatías, hipertensión arterial y arritmias. Abstract: Introduction: Approved drugs for attention deficit hyperactivity disorder (ADHD) in Spain are methylphenidate, lisdexamphetamine, atomoxetine and guanfacine. Due to adverse cardiovascular effects, mainly increased blood pressure and heart rate, its use in patients with known or undiagnosed heart disease may be controversial. Objective: To obtain a consensus document from the Spanish Society of Paediatric Cardiology and Congenital Heart Diseases (SECPCC) and experts from other Agencies and Societies as a guide for the paediatric cardiologist and physicians who treat children and adolescents with ADHD. Methodology: An analysis was performed on the bibliography and Clinical Practice Guidelines, technical data sheets approved by the Spanish Agency of Medicines and Health Devices, and the Spanish Ministry of Health Guidelines. A Working Group was formed, with a Coordinator, as well as members of the Clinical Cardiology Working Group and Arrhythmia Group of the SECPCC. This Group produced a preliminary document that was reviewed by a group of external experts and a group of internal experts of the SECPCC with a consensus being reached on the final document. Results: The recommendations of the SECPCC and the group of experts are presented on cardiovascular evaluation prior to treatment in children and adolescents with no known cardiovascular disease and with known cardiovascular disease.The recommendations of the SECPCC and the group of experts are also presented on the use of medications for ADHD in children and adolescents with cardiological symptoms with no evidence of heart disease, congenital heart disease, cardiomyopathy, Marfan syndrome and other aortic diseases, hypertension, and arrhythmias.

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.

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.

Cardiomyopathies are a heterogeneous group of inherited cardiac diseases characterized by progressive myocardium abnormalities associated with mechanical and/or electrical dysfunction. Massive genetic sequencing technologies allow a comprehensive genetic analysis to unravel the cause of disease. However, most identified genetic variants remain of unknown clinical significance due to incomplete penetrance and variable expressivity. Therefore, genetic interpretation of variants and translation into clinical practice remain a current challenge. We performed retrospective comprehensive clinical assessment and genetic analysis in six families, four diagnosed with arrhythmogenic cardiomyopathy, and two diagnosed with hypertrophic cardiomyopathy (HCM). Genetic testing identified three rare variants (two non-sense and one small indel inducing a frameshift), each present in two families. Although each variant is currently classified as pathogenic and the cause of the diagnosed cardiomyopathy, the onset and/or clinical course differed in each patient. New genetic technology allows comprehensive yet cost-effective genetic analysis, although genetic interpretation, and clinical translation of identified variants should be carefully done in each family in a personalized manner.

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.

Introducción y objetivos: El origen anómalo de una arteria coronaria en la arteria pulmonar (ACAPA) es una rara anomalía coronaria, cuya repercusión sobre la anatomía y la función cardiacas la hacen de gran interés. Describimos nuestra experiencia en el diagnóstico y el tratamiento quirúrgico de esta afección. Pacientes y métodos: Realizamos un estudio retrospectivo de los pacientes diagnosticados y tratados por ACAPA desde 1997 hasta el 2012 en nuestra institución. Resultados: Un total de 9 casos fueron atendidos en nuestro centro en un periodo de 15 años. El diagnóstico se sospechó en 6 pacientes por un soplo cardiaco, 3 comenzaron con insuficiencia cardiaca y uno con fibrilación ventricular y parada cardiaca. La corrección quirúrgica consistió en translocación de la arteria coronaria anómala desde la arteria pulmonar a la arteria aorta en los 8 pacientes. La función miocárdica mejoró en 2 de los 3 pacientes que la tenían comprometida, la supervivencia postoperatoria fue del 100%, un paciente falleció antes de la intervención. 7 pacientes presentaban algún grado de insuficiencia mitral, que disminuyó tras la corrección quirúrgica en 5 de ellos, se mantuvo igual en un paciente y requirió de sustitución valvular mitral en otro paciente. Conclusiones: Se evidencia que el ACAPA no es una afección de fácil diagnóstico; son muy importantes la sospecha clínica y el tratamiento precoz con el fin de evitar lesiones cardiacas graves.

[This corrects the article DOI: 10.1371/journal.pone.0167358.].

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)

Brugada syndrome (BrS) is a rare genetic cardiac arrhythmia that can lead to sudden cardiac death in patients with a structurally normal heart. Genetic variations in SCN5A can be identified in approximately 20-25% of BrS cases. The aim of our work was to determine the spectrum and prevalence of genetic variations in a Spanish cohort diagnosed with BrS.We directly sequenced fourteen genes reported to be associated with BrS in 55 unrelated patients clinically diagnosed. Our genetic screening allowed the identification of 61 genetic variants. Of them, 20 potentially pathogenic variations were found in 18 of the 55 patients (32.7% of the patients, 83.3% males). Nineteen of them were located in SCN5A, and had either been previously reported as pathogenic variations or had a potentially pathogenic effect. Regarding the sequencing of the minority genes, we discovered a potentially pathogenic variation in SCN2B that was described to alter sodium current, and one nonsense variant of unknown significance in RANGRF. In addition, we also identified 40 single nucleotide variations which were either synonymous variants (four of them had not been reported yet) or common genetic variants. We next performed MLPA analysis of SCN5A for the 37 patients without an identified genetic variation, and no major rearrangements were detected. Additionally, we show that being at the 30-50 years range or exhibiting symptoms are factors for an increased potentially pathogenic variation discovery yield.In summary, the present study is the first comprehensive genetic evaluation of 14 BrS-susceptibility genes and MLPA of SCN5A in a Spanish BrS cohort. The mean pathogenic variation discovery yield is higher than that described for other European BrS cohorts (32.7% vs 20-25%, respectively), and is even higher for patients in the 30-50 years age range.

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is a cardiac disease characterized by the presence of fibrofatty replacement of the right ventricular myocardium, which may cause ventricular arrhythmias and sudden cardiac death. Pathogenic mutations in several genes encoding mainly desmosomal proteins have been reported. Our aim is to perform genotype-phenotype correlations to establish the diagnostic value of genetics and to assess the role of mutation type in age-related penetrance in ARVC.Methods and resultsThirty unrelated Spanish patients underwent a complete clinical evaluation. They all were screened for PKP2, DSG2, DSC2, DSP, JUP and TMEM43 genes. A total of 70 relatives of four families were also studied. The 30 patients fulfilled definite disease diagnostic criteria. Genetic analysis revealed a pathogenic mutation in 19 patients (13 in PKP2, 3 in DSG2, 2 in DSP, and 1 in DSC2). Nine of these mutations created a truncated protein due to the generation of a stop codon. Familial assessment revealed 28 genetic carriers among family members. Stop-gain mutations were associated to a later age of onset of ARVC, without differences in the severity of the pathology.ConclusionsFamilial genetic analysis helps to identify the cause responsible for the pathology. In discrepancy with previous studies, the presence of a truncating protein does not confer a worse severity. This information could suggest that truncating proteins may be compensated by the normal allele and that missense mutations may act as poison peptides.

BACKGROUND:Long QT Syndrome is an inherited channelopathy leading to sudden cardiac death due to ventricular arrhythmias. Despite that several genes have been associated with the disease, nearly 20% of cases remain without an identified genetic cause. Other genetic alterations such as copy number variations have been recently related to Long QT Syndrome. Our aim was to take advantage of current genetic technologies in a family affected by Long QT Syndrome in order to identify the cause of the disease. METHODS:Complete clinical evaluation was performed in all family members. In the index case, a Next Generation Sequencing custom-built panel, including 55 sudden cardiac death-related genes, was used both for detection of sequence and copy number variants. Next Generation Sequencing variants were confirmed by Sanger method. Copy number variations variants were confirmed by Multiplex Ligation dependent Probe Amplification method and at the mRNA level. Confirmed variants and copy number variations identified in the index case were also analyzed in relatives. RESULTS:In the index case, Next Generation Sequencing revealed a novel variant in TTN and a large deletion in KCNQ1, involving exons 7 and 8. Both variants were confirmed by alternative techniques. The mother and the brother of the index case were also affected by Long QT Syndrome, and family cosegregation was observed for the KCNQ1 deletion, but not for the TTN variant. CONCLUSIONS:Next Generation Sequencing technology allows a comprehensive genetic analysis of arrhythmogenic diseases. We report a copy number variation identified using Next Generation Sequencing analysis in Long QT Syndrome. Clinical and familiar correlation is crucial to elucidate the role of genetic variants identified to distinguish the pathogenic ones from genetic noise.