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202. Pharmacological and device approach to therapy of inherited cardiac diseases associated with cardiac arrhythmias and sudden death

Author

Brugada, J., Brugada, R., and Brugada, P.

Abstract

A genetic origin in diseases like the long QT syndrome, the Brugada syndrome, or hypertrophic cardiomyopathy have been identified over the past years. These diseases have in common that they may result in sudden cardiac death of the patient. Recognition of patients based on their phenotype and application in clinical practice of the knowledge acquired on the genetic basis may have a major impact on how we approach them. In the long QT syndrome several mutations have been identified both in the sodium and in the potassium channels. The different electrophysiological effects of the mutations lead to a common phenotype: prolongation of the QT interval; but also to a common clinical impact: occurrence of malignant ventricular arrhythmias. Genetics should help us in treating in a more rational way our patients depending on the type of mutation. In the Brugada syndrome, mutations affecting the sodium channel have been so far identified. The results are electrophysiologically opposite to the ones observed in the long QT syndrome. Thus different mutations in the same gene lead to different functional consequences. Again, identification and study of the right mutation may lead to a more rational treatment directed to correct the malfunction of the channel.

Published
2000
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206. Cardiovascular translational medicine (IV): The genetic basis of malignant arrhythmias and cardiomyopathies

Author

oscar campuzano, Sarquella-Brugada G, Brugada R, Brugada P, Brugada J, Cardio-vascular diseases, and Internal Medicine Specializations

Subjects
Potassium Channels, cardiac, genetics, Calcium Channels, Arrhythmias, Cardiomyopathies, Ion Channels
Abstract

The remarkable advances that have taken place in biomedicine over the past 50 years have resulted in dramatic improvements in the prevention, diagnosis and treatment of many diseases. Although cardiology has adopted these advances at a relatively slow pace, today it is fully immersed in this revolution and has become one of the most innovative medical specialties. Research is continuing to give rise to new developments in genetics and molecular biology that lead, almost daily, to innovative ways of preventing, diagnosing and treating the most severe forms of heart disease. Consequently, it is essential that clinical cardiologists have some basic knowledge of genetics and molecular biology as these disciplines are having an increasing influence on clinical practice.

207. Brugada syndrome: 12 Years of progression

Author

Hong, K., Antzelevitch, C., Brugada, P., JOSEP BRUGADA, Ohe, T., Brugada, R., and Internal Medicine Specializations

Subjects
Male, Electrocardiography, Heart Diseases, Humans, Arrhythmias, Cardiac, Female, Brugada syndrome, genetics, cardiovascular diseases, Syndrome, Sodium Channels, NAV1.5 Voltage-Gated Sodium Channel, suddendeath
Abstract

Brugada syndrome is increasingly being recognized in clinical medicine. What started as an electrocardiographic curiosity has become an important focus of attention for individuals working in the different disciplines related to sudden cardiac death, from basic scientists to clinical cardiac electrophysiologists. In just 12 years, since the description of the disease, clinically relevant information is continuously being provided to physicians to help protect the individuals with Brugada syndrome to the best of our ability. And this information has been gathered thanks to the effort of hundreds of basic scientists, physicians and patients who continue to give their time, effort and data to help understand how the electrocardiographic pattern may cause sudden cardiac death. There are still many unanswered questions, both at the clinical and basic field. However, with the further collection of data, the longer follow-up and the continued interest from the basic science world we will have the necessary tools to the successful unraveling of the disease.

211. Short QT syndrome

Author

Campuzano, O., Sarquella-Brugada, G., ELENA ARBELO, Brugada, J., and Brugada, R.

214. Post-mortem genetic analysis in juvenile cases of sudden cardiac death

Author

Campuzano O, Sanchez-Molero O, Allegue C, Coll M, Irene Mademont-Soler, Selga E, Ferrer-Costa C, Mates J, Iglesias A, Sarquella-Brugada G, Cesar S, Brugada J, Castellà J, Medallo J, and Brugada R

Subjects
Adolescent, Forensics, Genetics, Next Generation Sequencing, Paediatric, Sudden cardiac death
Abstract

The reason behind a sudden death of a young individual remains unknown in up to 50% of postmortem cases. Pathogenic mutations in genes encoding heart proteins are known to cause sudden cardiac death.

219. Time from electrocardiographic diagnosis of st-elevation myocardial infarction to guidewire crossing in patients transferred to a hospital for primary angioplasty: Factors associated with delay,Factores asociados a retrasos de tiempo desde el electrocardiograma diagnóstico hasta el paso de guía en el infarto agudo de miocardio con elevación del segmento st transferido para angioplastia primaria

Author

Aboal, J., Ramos, R., Loma-Osorio, P., Núñez, M., Marc Comas-Cufí, Iglesies, J., Moral, S., Bosch, D., Martí-Lluch, R., Alves-Cabratosa, L., and Brugada, R.

221. Brugada syndrome

Author

Brugada R, oscar campuzano, Brugada P, Brugada J, Hong K, Internal Medicine Specializations, Cardio-vascular diseases, and Clinical sciences

Subjects
Genetic Markers, General Medicine, Review, Arrhythmias, sudden cardiac death, NAV1.5 Voltage-Gated Sodium Channel, Electrocardiography, Phenotype, Heart Rate, Predictive Value of Tests, Risk Factors, Mutation, Animals, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Brugada Syndrome
Abstract

Brugada syndrome is a rare cardiac arrhythmia characterized by electrocardiographic right bundle branch block and persistent ST-segment elevation in the right precordial leads. It is associated with ventricular fibrillation and a high risk for sudden cardiac death, predominantly in younger males with structurally normal hearts. Patients can remain asymptomatic, and electrocardiographic patterns can occur both spontaneously or after pharmacological induction. So far, several pathogenic genes have been identified as associated with the disease, but SCN5A is the most prevalent one. Two consensus reports to define the diagnostic criteria, risk stratification, and management of patients have been published in the last few years. This brief review focuses on the recent clinical diagnosis, genetic basis, and advances in pharmacological treatment of Brugada syndrome.

223. Use of intravenous antiarrhythmics to identify concealed Brugada syndrome

Author

Brugada Ramon

Subjects
Brugada syndrome, class I antiarrhythmics, Medicine (General), R5-920
Abstract

Abstract Cardiology has recently witnessed the production of an overwhelming amount of data through the advances made in genetics and molecular biology research. Understanding of genetics has tremendous potential to aid in the prevention, diagnosis and treatment of the majority of diseases. Despite the high level of publicity for research discoveries, clinicians have had difficulty in discriminating between what is still basic research and what can be applied to patients. The fact is that we still lack the technology to perform genetic testing in a time frame that is acceptable to clinicians. Meanwhile, then, the only option is to rely on clinical tests that can help us better stratify the individuals at risk for a disease. For example, Brugada syndrome has benefited tremendously from genetics and molecular biology since its initial description in 1992. Genetics will provide a more definitive diagnosis for the disease in the future. For the time being, though, research has shown that the administration of an intravenous class I antiarrhythmic is very useful in identifying patients with a concealed form of the disease.

Published
2000
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229. P579 Novel insights into the regulatory mechanisms of scn5a expression.

Author

Tarradas, A, Pinsach-Abuin, M, Llora, O, Beltran-Alvarez, P, Brugada, R, and Pagans, S

Subjects
PROTEIN expression, SODIUM channels, HEART cells, GENETIC mutation, SOMATIC cell nuclear transfer, ARRHYTHMIA
Abstract

Brugada Syndrome (BrS) is a life-threating arrhythmogenic disease associated with a high risk of Sudden Cardiac Death. Genetic alterations in SCN5A, which encodes the alpha subunit of the cardiac voltage-gated sodium channel (Nav1.5), are the most common cause of BrS. Nav1.5 channel is responsible for the rapid influx of sodium ions that initiate the propagation of the action potential in cardiomyocytes. However, mutations in SCN5A gene only explain 20-25% of the cases with BrS. Our working hypothesis is that a deregulation of SCN5A expression could cause BrS and explain, at least in part, some cases of BrS with no mutation identified. Nevertheless, little is known regarding the regulation of SCN5A expression. Therefore, it is the goal of this study to gain insight into the molecular mechanisms that regulate SCN5A expression at the transcriptional level, and how alterations of these mechanisms contribute to cardiac arrhythmias.The human SCN5A promoter contains putative binding sites for the zinc finger transcription factor GATA-4. We performed GATA-4 overexpression and knockdown studies in cardiac H9c2 cells, and analyzed the effect on the SCN5A promoter by luciferase reporter experiments and real-time PCR. Our data showed that GATA-4 is a novel transcriptional activator of the SCN5A promoter. We also analyzed the effect of other GATA family members, GATA-5 and -6. Whereas GATA-6 did not have any effect on the SCN5A promoter, GATA-5 increased SCN5A transcriptional activity although to a less extent than GATA-4. Moreover, we observed that GATA-4 significantly synergizes with GATA-5 on SCN5A transcriptional activation. Chromatin Immunoprecipitation (ChIP) experiments from human cardiac tissue showed that GATA-4 and GATA-5 bind to the SCN5A proximal promoter region, confirming a critical role of these factors in regulating SCN5A expression in vivo. Our current experiments are also focused on studying the interaction between GATA-4 and GATA-5 transcription factors.We performed co-transfection experiments of GATA-4 with p300 acetyltransferase and observed a further increase on SCN5A promoter activity. These results suggest that GATA-4 transcriptional activity on the SCN5A promoter is modulated by acetylation. We are now investigating which histones acetyltransferases (HDACs) could participate in the activity of GATA-4 on the SCN5A promoter.Our findings provide novel insights on the regulation of Nav1.5 expression, which will ultimately contribute to further understanding unexplored causes of BrS and other type of cardiac arrhythmias. [ABSTRACT FROM AUTHOR]

Published
2014
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230. P111 SCN1Bb: a new susceptibly gene underlying LQT syndrome.

Author

Riuro, H, Campuzano, O, Beltran-Alvarez, P, Arbelo, E, Iglesias, A, Brugada, J, Perez, GJ, Scornik, F, and Brugada, R

Subjects
HEART cells, HEART diseases, GENETIC mutation, APPROXIMATION theory, LONG QT syndrome, ION channels, SODIUM channels
Abstract

Long QT Syndrome (LQTS) is a rare inherited cardiac disorder with a high risk of sudden cardiac death in a structurally normal heart. To date, pathogenic mutations have been described as responsible for approximately 70-75% of LQTS patients, mainly in ion channel genes. Mutations in genes encoding the sodium channel α subunit or other regulatory proteins, affecting cardiac sodium current, have been previously related to LQTS. Five sodium channel β subunits have been identified, which are encoded by four genes (SCN1B-4B). Pathogenic mutations in the SCN4B gene, but not in other β subunits, have been reported in LQTS. We tested whether mutations in SCN1B-4B could be responsible for LQTS in patients without mutations in the common LQTS-related genes.We screened for mutations in SCN1B-4B genes in 30 non-related patients clinically diagnosed with LQTS carrying no mutations in the major LQTS-related genes. The screening revealed a novel mutation in the SCN1B gene in an 8-year-old boy. The base change resulted in an amino acid variation from proline to threonine in the alternative C-terminus of the sodium channel β1 subunit (β1b).Using the patch clamp technique, we measured sodium current density, and Nav1.5 gaiting properties, in HEK cells transiently transfected with Nav1.5 and β1b subunits. Our electrophysiological analysis revealed that the mutant β1b altered Nav1.5 function by shifting the window current to negative potentials, increasing recovery from inactivation, decreasing slow inactivation, and increasing late sodium current. In addition, we recorded action potentials from mouse atrial cardiomyocytes, HL-1 cells, transfected with β1b subunits. These experiments revealed that the action potential duration significantly increased when the mutant β1b was overexpressed compared to β1bWT.These findings suggest that the mutation in β1b could explain the LQTS in our patient, revealing SCN1Bb as a new susceptibility gene for LQTS. Our results confirm the importance of sodium channel β subunits in the modulation of cardiac sodium channel. In addition, they highlight the need for further investigation to detect new candidate genes underlying the LQTS patients that currently remain without genetic diagnosis. [ABSTRACT FROM AUTHOR]

Published
2014
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231. P395 The truncated plakophilin-2 protein localizes in the intercalated disc and induces cardiac fibrosis in a transgenic mouse model.

Author

Moncayo-Arlandi, J, Diez-Juan, A, Casado, M, and Brugada, R

Subjects
GENETIC mutation, TRANSGENIC mice, HEART fibrosis, CARDIOMYOPATHIES, HEART cells, LABORATORY mice
Abstract

Objective: Plakophilin-2 (PKP2) mutations represent 50% of desmosomal mutations associated to Arrythmogenic Right Ventricular Cardiomyopathy (ARVC) in humans. Many of these mutations cause a truncated protein PKP2. However, the mechanism whereby truncated PKP2 causes disease is unclear. The aim of this study is to unravel the molecular and cellular mechanism of truncated PKP2 in ARVD pathogenesis.Methods: For this study, we developed a transgenic mouse model containing a truncated PKP2 (329 of 837aa native protein) under specific cardiac promoter (α-MHC). We have studied alterations in the expression and the localization of different desmosomal proteins. In addition, we have studied alterations in cardiac morphology and size. We have also analyzed the histological phenotype using hematoxylin-eosin and Masson trichrome staining and oil red and Sirius red methods to detect the fatty and fibrous tissue. The level of cardiomyocytes early apoptosis has been analyzed by TUNEL. Finally, the ultrastructure of the intercalated disc has been analyzed using a transmission electronic microscopy.Results: The truncated PKP2 was localized in the intercalated disc and a small fraction in the cytoplasm of cardiomyocytes. Interestingly, an intense signal of truncated protein was found in the nucleus of some cardiomyocytes. The expression and localization of distinct desmosomal proteins was similar in hearts from wildtype and transgenic mice. We do not detect any cardiac hypertrophy in the transgenic mice when it was compared with wildtype mice (0.65 ± 0.11 vs 0.71 ± 0.15; respectively). We have observed fibrosis in cardiac tissue in 2 of 30 total transgenic mice analyzed (<7%). This is characterized by the presence of fibrous tissue with absence of adipocytes and apoptosis. Ultrastructure of desmosome reveals micro-breakages in the intercalated discs of cardiomyocytes from transgenic mice including the ones without fibrous tissue replacement.Conclusions: Although a low frequency of fibrosis was found, the presence of micro-breakages suggests that the truncated PKP2 reduces the cardiomyocytes adhesion/viability and increases the predisposition to the development of fibrosis. We can hypothesize that presence of truncated PKP2 in the intercalated disc could compete with the endogenous PKP2 binding sites, affecting to the cardiac tissue integrity. [ABSTRACT FROM PUBLISHER]

Published
2014
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232. P389 Role of truncated plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy.

Author

Alcalde, M, Campuzano, O, Beltran-Alvarez, P, Pagans, S, Verges, M, and Brugada, R

Subjects
CYTOSKELETON, RIGHT heart ventricle, CARDIOMYOPATHIES, CELL membranes, CARDIAC arrest, PHENOTYPES, BIOLOGICAL variation
Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare cardiac disease characterized by fibrofatty replacement of the right ventricular myocardium, which may cause ventricular arrhythmias and sudden cardiac death (SCD).Mutations in genes encoding desmosome proteins have been associated with ARVC: plakophilin-2 (PKP2), desmoplakin (DSP), desmocolin-2 (DSC2), desmoglein-2 (DSG2) and plakoglobin (PG). Plakophilin-2 (PKP2) is the most prevalent gene associated with ARVC, especially stop-gained mutations, which lead to truncated PKP2 (PKP2TR).Our recent genetic studies have shown that PKP2TR is associated to a later age of ARVC onset (37 years old) compared to missense carriers (27 years old). This raised an alternative hypothesis as to the pathogenicity of missense and truncated proteins, and their role in phenotype. We hypothesize that PKP2TR is associated with trafficking to the plasma membrane, which can be compensated by the normal allele; while missense variations may act through a dominant negative effect, disrupting the function of the wild type protein since they are mostly incorporated to desmosome.To explore this hypothesis, we performed an in vitro study with the three following aims: (1) to examine the subcellular location of PKP2TR forms in the in HL-1 cardiac-like cells, (2) how PKP2TR length affect to their proper traffic to plasma membrane and (3) PKP2TR effect on desmosome assembly. Based on mutations associated to ARVC in our genetic study, we selected four PKP2TR versions (at amino acids 91, 412, 637 and 734), which were transiently co-transfected in HL-1 cells with major desmosome proteins (DSP,DSC2, DSG2 and PG).We observed that these PKP2TR forms are not localized efficiently to the plasma membrane; PKP2TR-91 remained diffuse in the cytoplasm; PKP2TR-412 was retained in the endoplasmic reticulum displaying a dotted pattern. In contrast PKP2TR-637 and PKP2TR-734 were only partially located to the plasma membrane with a major fraction still cytosolic. We also observed that all PKP2TR caused deficient localization of other desmosome proteins, especially DSP, which requires PKP2 for its proper trafficking to the plasma membrane.Thus, these data suggest that the degree of the truncation in PKP2 does not correlate with a clear effect in desmosome assembly. Results clearly show that PKP2TR forms are not efficiently incorporated to the plasma membrane, and they affect desmosome assembly. These data favour the idea that PKP2TR may be associated to trafficking defect, while missense mutations may act in a dominant negative way disrupting function of the wild-type protein. [ABSTRACT FROM PUBLISHER]

Published
2014
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233. P335 Sudden unexplained death in Catalonia: comprehensive genetic analysis in post-mortem samples.

Author

Sanchez-Molero, OE, Campuzano, O, Allegue, C, Selga, E, Mademont, I, Coll, M, Mates, J, Iglesias, A, Medallo, J, and Brugada, R

Subjects
CARDIAC arrest, AUTOPSY, CARDIOMYOPATHIES, GENETIC mutation, DNA
Abstract

Purpose: Cardiovascular pathologies are the main cause of sudden death in developed countries. In population older than 50 years old, most deaths are due to coronary disease alterations, in the young deaths may be caused by "monogenetic disorders", channelopathies, or cardiomyopathies. Genetic analysis is not routinely performed in autopsy protocol when a cause of death is not identified in the young. In recent years the development of next generation sequencing (NGS) technology allows the investigation of high number of genes in a short period of time at low cost. We launched the MOSCAT project, a prospective post-mortem study that aims to identify the genetic cause of death in cases that remains without a conclusive diagnosis after a complete autopsy. Methods: Our cohort included a total of 88 cases: <50 years old, and no-conclusive cause of death after complete autopsy investigation. We divided the cohort into two groups, depending on DNA quality for NGS analysis. The first group included 59 samples with low quality. The main seven arrhythmogenic genes (KCNQ1, KCNH2, KCNE1, KCNE2, KCNE3, RYR2 and SCN5A) were analyzed using Sanger method. The second group included 43 samples analyzed by NGS, a total of 55 genes associated with SCD were analyzed. Potentially pathogenic role was determined when minor allele frequency (MAF) was less than 1% and at least one in silico prediction. A total of 14 samples were analyzed using both methods as internal control. Results: Our cohort of 88 samples showed a gender ratio of 2:1 (men: women respectively). In group 1 (sanger, 59 samples) we identified 30% arrythmogenic mutation carriers. In group 2 (NGS, 43 samples) we identified 15% arrythmogenic mutations and 85% associated with structural cardiomyopathies. Acording to age in group 1 we identified 27% mutations in patients younger than 35 and 34% in older than 35. By NGS we identified 50% arrythmogenic mutations and 50% structural mutations in less than 35 and 40% arrythmogenic mutations and 60% structural mutations in older than 35. Conclusions: In patients younger than 50, we identified arrythmogenic mutations in 25% and structural mutations in 70% of cases studied. Nearly 30% of post-mortem cases minor than 50 years with a no-conclusive cause of death carry a potential pathogenic variation that could explain the death. NGS technology adds additional information and may be useful in the identification of genetic causality. We believe that genetic analysis should be included in routine forensic guidelines when a no-conclusive cause of death arises, especially in cases under 35 years old. [ABSTRACT FROM PUBLISHER]

Published
2014
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236. To the editor.

Author

Green M, Gollob M, Sternick EB, Oliva A, Magalhaes LP, Gerken L, Hong K, Santana O, Brugada P, Brugada J, and Brugada R

Published
2006
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240. Malignant Arrhythmogenic Role Associated with RBM20: A Comprehensive Interpretation Focused on a Personalized Approach

Author

Jordà, Paloma, Toro, Rocío, Diez, Carles, Salazar-Mendiguchía, Joel, Fernandez-Falgueras, Anna, Perez-Serra, Alexandra, Coll, Monica, Puigmulé, Marta, Arbelo, Elena, García-Álvarez, Ana, Sarquella-Brugada, Georgia, Cesar, Sergi, Tiron, Coloma, Iglesias, Anna, Brugada, Josep, Brugada, Ramon, Campuzano, Oscar, [Jordà,P, Arbelo,E, García-Álvarez,A, Brugada,J] Cardiology Department, Hospital Clinic, University of Barcelona-IDIBAPS, Barcelona, Spain. [Toro,R] Medicine Department, School of Medicine, University of Cadiz, Cadiz, Spain. [Toro,R] Biomedical Research and Innovation Institute of Cadiz (INiBICA), Cadiz, Spain. [Diez,C, Salazar-Mendiguchía,J] Cardiovascular Diseases Research Group Bellvitge Biomedical Research Institute (IDIBELL) Hospitalet de Llobregat, Barcelona, Spain. [Diez,C] Advanced Heart Failure and Heart Transplant Unit Department of Cardiology Bellvitge University Hospital Hospitalet de Llobregat, Barcelona, Spain. [Fernandez-Falgueras,A, Perez-Serra,A, Coll,M, Puigmulé,M, Iglesias,A, Brugada,R, Campuzano,O] Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain. [Perez-Serra,A, Brugada,J, Campuzano,O] Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. [Sarquella-Brugada,G, Cesar,S, Campuzano,O] Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Cardiology Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain. [Sarquella-Brugada,G, Campuzano,O] Medical Science Department, School of Medicine, University of Girona, Girona, Spain. [Tiron,C, Brugada,R] Cardiology Service, Hospital Josep Trueta, University of Girona, Girona, Spain., and This work was supported by Obra Social 'La Caixa Foundation' (LCF/PR/GN16/50290001 and LCF/PR/GN19/50320002), Fondo Investigacion Sanitaria (FIS PI16/01203 and FIS, PI17/01690) from Instituto Salud Carlos III (ISCIII), and 'Fundacio Privada Daniel Bravo Andreu'. CIBERCV is an initiative of the ISCIII, Spanish Ministry of Economy and Competitiveness.

Subjects
RBM20, Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], Anatomy::Musculoskeletal System::Muscles [Medical Subject Headings], Dilated cardiomyopathy, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Nucleoproteins::RNA-Binding Proteins [Medical Subject Headings], Supresión genética, Genética, Arritmias cardíacas, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Sudden cardiac death, Cardiomiopatía dilatada, Diseases::Cardiovascular Diseases::Heart Diseases::Arrhythmias, Cardiac [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::RNA Processing, Post-Transcriptional::RNA Splicing [Medical Subject Headings], Muerte súbita cardíaca, Diseases::Cardiovascular Diseases::Heart Diseases::Cardiomyopathies [Medical Subject Headings], Genetics, Phenomena and Processes::Genetic Phenomena::Genotype [Medical Subject Headings], Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::RNA Processing, Post-Transcriptional::RNA Splicing::Alternative Splicing [Medical Subject Headings], Arrhythmia
Abstract

The RBM20 gene encodes the muscle-specific splicing factor RNA-binding motif 20, a regulator of heart-specific alternative splicing. Nearly 40 potentially deleterious variants in RBM20 have been reported in the last ten years, being found to be associated with highly arrhythmogenic events in familial dilated cardiomyopathy. Frequently, malignant arrhythmias can be a primary manifestation of disease. The early recognition of arrhythmic genotypes is crucial in avoiding lethal episodes, as it may have an impact on the adoption of personalized preventive measures. Our study performs a comprehensive update of data concerning rare variants in RBM20 that are associated with malignant arrhythmogenic phenotypes with a focus on personalized medicine. Yes

Published
2021

241. The brain–heart interaction in epilepsy: implications for diagnosis, therapy, and SUDEP prevention

Author

Giorgio Costagliola, Monica Coll, Ramon Brugada, Pasquale Parisi, Alessandro Orsini, Pasquale Striano, Institut Català de la Salut, [Costagliola G, Orsini A] Pediatric Clinic, Santa Chiara's University Hospital, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. [Coll M] Centre de Genètica Cardiovascular, Institut d’Investigació Biomèdica de Girona (IDIBGI), Salt, Spain. [Brugada R] Centre de Genètica Cardiovascular, Institut d’Investigació Biomèdica de Girona (IDIBGI), Salt, Spain. Departament de Ciències Mèdiques, Facultat de Medicina, Universitat de Girona, Girona, Spain. Centro Investigación Biomédica en Red: Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. Servei de Cardiologia, Hospital Universitari de Girona Dr. Josep Trueta, Institut Català de la Salut (ICS), Girona, Spain. [Parisi P] Chair of Pediatrics, NESMOS Department, Faculty of Medicine and Psychology, Sapienza University, Sant' Andrea Hospital, Rome, Italy. [Striano P] IRCCS Istituto Giannina Gaslini, Genova, Italy. Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy, and Hospital Universitari de Girona Dr Josep Trueta

Subjects
0301 basic medicine, Review, Epilepsy, 0302 clinical medicine, Heart Rate, Risk Factors, Neural Pathways, Medicine, Heart rate variability, Anticonvulsants, Brain, Heart Diseases, Humans, Sudden Unexpected Death in Epilepsy, Cause of death, education.field_of_study, Mort sobtada, General Neuroscience, Cardiovascular Diseases::Heart Diseases [DISEASES], Cardiology, epilepsy, SUDEP, autonomic system, RC321-571, medicine.medical_specialty, Population, Reviews, Neurosciences. Biological psychiatry. Neuropsychiatry, Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Epilepsy [DISEASES], enfermedades cardiovasculares::enfermedades cardíacas [ENFERMEDADES], Sudden death, 03 medical and health sciences, Internal medicine, Heart rate, Pathological Conditions, Signs and Symptoms::Pathologic Processes::Death::Death, Sudden [DISEASES], afecciones patológicas, signos y síntomas::procesos patológicos::muerte::muerte súbita [ENFERMEDADES], Asystole, RC346-429, education, Cor - Malalties, business.industry, medicine.disease, Comorbidity, Epilèpsia, 030104 developmental biology, enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::epilepsia [ENFERMEDADES], Neurology. Diseases of the nervous system, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Epilèpsia; Malalties cardiaques; Mort sobtada Epilepsia; Enfermedades cardiacas; Muerte súbita Epilepsy; Heart disease; Sudden death The influence of the central nervous system and autonomic system on cardiac activity is being intensively studied, as it contributes to the high rate of cardiologic comorbidities observed in people with epilepsy. Indeed, neuroanatomic connections between the brain and the heart provide links that allow cardiac arrhythmias to occur in response to brain activation, have been shown to produce arrhythmia both experimentally and clinically. Moreover, seizures may induce a variety of transient cardiac effects, which include changes in heart rate, heart rate variability, arrhythmias, asystole, and other ECG abnormalities, and can trigger the development of Takotsubo syndrome. People with epilepsy are at a higher risk of death than the general population, and sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Although the cause of SUDEP is still unknown, cardiac abnormalities during and between seizures could play a significant role in its pathogenesis, as highlighted by studies on animal models of SUDEP and registration of SUDEP events. Recently, genetic mutations in genes co-expressed in the heart and brain, which may result in epilepsy and cardiac comorbidity/increased risk for SUDEP, have been described. Recognition and a better understanding of brain-heart interactions, together with new advances in sequencing techniques, may provide new insights into future novel therapies and help in the prevention of cardiac dysfunction and sudden death in epileptic individuals.

Published
2021
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242. Genome-wide association analyses identify novel Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Author

Barc, Julien, Tadros, Rafik, Glinge, Charlotte, Chiang, David Y., Jouni, Mariam, Simonet, Floriane, Jurgens, Sean J., Baudic, Manon, Nicastro, Michele, Potet, Franck, Offerhaus, Joost A., Walsh, Roddy, Choi, Seung Hoan, Verkerk, Arie O., Mizusawa, Yuka, Anys, Soraya, Minois, Damien, Arnaud, Marine, Duchateau, Josselin, Wijeyeratne, Yanushi D., Muir, Alison, Papadakis, Michael, Castelletti, Silvia, Torchio, Margherita, Ortuño, Cristina Gil, Lacunza, Javier, Giachino, Daniela F., Cerrato, Natascia, Martins, Raphaël P., Campuzano, Oscar, Van Dooren, Sonia, Thollet, Aurélie, Kyndt, Florence, Mazzanti, Andrea, Clémenty, Nicolas, Bisson, Arnaud, Corveleyn, Anniek, Stallmeyer, Birgit, Dittmann, Sven, Saenen, Johan, Noël, Antoine, Honarbakhsh, Shohreh, Rudic, Boris, Marzak, Halim, Rowe, Matthew K., Federspiel, Claire, Le Page, Sophie, Placide, Leslie, Milhem, Antoine, Barajas-Martinez, Hector, Beckmann, Britt-Maria, Krapels, Ingrid P., Steinfurt, Johannes, Winkel, Bo Gregers, Jabbari, Reza, Shoemaker, Moore B., Boukens, Bas J., Škorić-Milosavljević, Doris, Bikker, Hennie, Manevy, Federico, Lichtner, Peter, Ribasés, Marta, Meitinger, Thomas, Müller-Nurasyid, Martina, Strauch, Konstantin, Peters, Annette, Schulz, Holger, Schwettmann, Lars, Leidl, Reiner, Heier, Margit, Veldink, Jan H., van den Berg, Leonard H., Van Damme, Philip, Cusi, Daniele, Lanzani, Chiara, Rigade, Sidwell, Charpentier, Eric, Baron, Estelle, Bonnaud, Stéphanie, Lecointe, Simon, Donnart, Audrey, Le Marec, Hervé, Chatel, Stéphanie, Karakachoff, Matilde, Bézieau, Stéphane, London, Barry, Tfelt-Hansen, Jacob, Roden, Dan, Odening, Katja E., Cerrone, Marina, Chinitz, Larry A., Volders, Paul G., van de Berg, Maarten P., Laurent, Gabriel, Faivre, Laurence, Antzelevitch, Charles, Kääb, Stefan, Arnaout, Alain Al, Dupuis, Jean-Marc, Pasquie, Jean-Luc, Billon, Olivier, Roberts, Jason D., Jesel, Laurence, Borggrefe, Martin, Lambiase, Pier D., Mansourati, Jacques, Loeys, Bart, Leenhardt, Antoine, Guicheney, Pascale, Maury, Philippe, Schulze-Bahr, Eric, Robyns, Tomas, Breckpot, Jeroen, Babuty, Dominique, Priori, Silvia G., Napolitano, Carlo, Defaye, Pascal, Anselme, Frédéric, Darmon, Jean Philippe, Wiart, François, de Asmundis, Carlo, Brugada, Pedro, Brugada, Ramon, Arbelo, Elena, Brugada, Josep, Mabo, Philippe, Behar, Nathalie, Giustetto, Carla, Molina, Maria Sabater, Gimeno, Juan R., Hasdemir, Can, Schwartz, Peter J., Crotti, Lia, McKeown, Pascal P., Sharma, Sanjay, Behr, Elijah R., Haissaguerre, Michel, Sacher, Frédéric, Rooryck, Caroline, Tan, Hanno L., Remme, Carol A., Postema, Pieter G., Delmar, Mario, Ellinor, Patrick T., Lubitz, Steven A., Gourraud, Jean-Baptiste, Tanck, Michael W., George, Alfred L., MacRae, Calum A., Burridge, Paul W., Dina, Christian, Probst, Vincent, Wilde, Arthur A., Schott, Jean-Jacques, Redon, Richard, Bezzina, Connie R., KORA-Study Group, Nantes Referral Ctr Inherited Card, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Santé - François Bonamy, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Amsterdam UMC - Amsterdam University Medical Center, The MINE study (J.H.V.) has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 772376—EScORIAL). The collaboration project is cofunded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public–private partnerships. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355. The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum München—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. J. Barc is supported by the research program Etoiles montantes des Pays de la Loire REGIOCARD RPH081-U1087-REG-PDL, ANR JCJC LEARN (R21006NN, RPV21014NNA) and by the H2020-MSCA-IF-2014 Program of the European Commission (RISTRAD-661617). R.T. is supported by the Canadian Heart Rhythm Society’s George Mines Award, the European Society of Cardiology research award, and the Philippa and Marvin Carsley Cardiology Chair. D.Y.C. is supported by Fondation Leducq and National Institutes of Health (NIH) NHGRI T32 (no. 1T32HG010464-01). M. Baudic was supported by IRP—VERACITIES—New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES, an I-SITE NExT health and engineering initiative (Ecole Centrale and Nantes University) and by the IRP—GAINES—Genetic Architecture IN cardiovascular disEaSes funded by INSERM and CNRS. R.W. is supported by an Amsterdam Cardiovascular Sciences fellowship. S.C. is supported by the NHLBI BioData Catalyst Fellows Program. C.A.R. is supported by Fondation Leducq, the Dutch Heart Foundation (CVON PREDICT2) and the Innovational Research Incentives Scheme Vidi grant from the Netherlands Organisation for Health Research and Development (ZonMw, 91714371). Y.D.W. is supported by the Robert Lancaster Memorial Fund. M.P. is supported by Cardiac Risk in the Young. S.V.D. is supported by Wetenschappelijk Fonds Willy Gepts VUB-UZ Brussel, project ‘Unravelling the molecular genetic pathways of Brugada Syndrome by cardiomics research’, VUB IRP project ‘IMAGica: an Integrative personalized Medical Approach for Genetic diseases, Inherited Cardia Arrhythmias as a model’ and Innoviris BRIDGE 2017, project ‘IGenCare: Integrated Personalised Medical Genomics Care Solution for Patients with Rare Genetic Diseases’. S.H. is supported by the Barts BRC. B.R. is supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). B.G.W. is supported by the Danish Heart Foundation. M.B.S. is supported by K23HL127704. Project MinE Belgium was supported by a grant from IWT (no. 140935), the ALS Liga België, the National Lottery of Belgium and the KU Leuven Opening the Future Fund. D.C. and C.L. are supported by HYPERGENES (HEALTH-F4-2007). D.R. is supported by R01 HL149826, P50 GM115305. P.J.S. acknowledges the support of Leducq Foundation for Cardiovascular Research grant 18CVD05. P.V.D. is supported by the Netherlands CardioVascular Research Initiative (CVON PREDICT2). C.A. is supported by NIH HL47678 and HL138103, W.W. Smith Charitable Trust and Wistar Morris Fund. M.B. is Supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). P.D.L. is supported by UCL/UCLH Biomedicine NIHR and Barts BRC. B.L. is supported by GOA—Antigone 33933. J.B. is supported by a Senior Clinical Fellowship of the Flemish Science Foundation (FWO). E.B. is supported by the British Heart Foundation including BHF Clinical Research Training Fellowship (FS/11/71/28918: Future diagnostic role and new genetic loci in SADS), Cardiac Risk in the Young and Robert Lancaster Memorial fund sponsored by McColl’s Ltd. Retail Group. H.L.T. is supported by the European Union’s Horizon 2020 research and innovation program under acronym ESCAPE-NET, registered under grant agreement no. 733381, and the Dutch Heart Foundation (CVON RESCUED and PREDICT2 projects). M.D. is supported by NIH-RO1 HL134328. P.T.E. was supported by the Fondation Leducq (14CVD01), the NIH (1RO1HL092577, R01HL128914, K24HL105780), the American Heart Association (18SFRN34110082) and by a research grant from Bayer AG to the Broad Institute. S.A.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. J.-B.G. received a grant from the Fédération Française de Cardiologie (PREVENT project). A.L.G. is supported by the Fondation Leducq. C.A.M.R. is supported by the Leducq Foundation and Burroughs Wellecome Fund. A.A.W. is supported by the Dutch Heart Foundation (CVON PREDICT2 project). J.-J.S. is supported by the Fondation pour la Recherche Médicale (DEQ20140329545). R.R. and P.G. are supported by the National Agency for Research (ANR-GENSUD-14-CE10-0001). C.R.B. is supported by the Dutch Heart Foundation (CVON PREDICT2 project), the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610) and Fondation Leducq (17CVD02)., Barc, J, Tadros, R, Glinge, C, Chiang, D, Jouni, M, Simonet, F, Jurgens, S, Baudic, M, Nicastro, M, Potet, F, Offerhaus, J, Walsh, R, Hoan Choi, S, Verkerk, A, Mizusawa, Y, Anys, S, Minois, D, Arnaud, M, Duchateau, J, Wijeyeratne, Y, Muir, A, Papadakis, M, Castelletti, S, Torchio, M, Gil Ortuño, C, Lacunza, J, Giachino, D, Cerrato, N, Martins, R, Campuzano, O, Van Dooren, S, Thollet, A, Kyndt, F, Mazzanti, A, Clémenty, N, Bisson, A, Corveleyn, A, Stallmeyer, B, Dittmann, S, Saenen, J, Noël, A, Honarbakhsh, S, Rudic, B, Marzak, H, Rowe, M, Federspiel, C, Le Page, S, Placide, L, Milhem, A, Barajas-Martinez, H, Beckmann, B, Krapels, I, Steinfurt, J, Gregers Winkel, B, Jabbari, R, Shoemaker, M, Boukens, B, Škorić-Milosavljević, D, Bikker, H, Manevy, F, Lichtner, P, Ribasés, M, Meitinger, T, Müller-Nurasyid, M, Group, K, Veldink, J, van den Berg, L, Van Damme, P, Cusi, D, Lanzani, C, Rigade, S, Charpentier, E, Baron, E, Bonnaud, S, Lecointe, S, Donnart, A, Le Marec, H, Chatel, S, Karakachoff, M, Bézieau, S, London, B, Tfelt-Hansen, J, Roden, D, Odening, K, Cerrone, M, Chinitz, L, Volders, P, van de Berg, M, Laurent, G, Faivre, L, Antzelevitch, C, Kääb, S, Al Arnaout, A, Dupuis, J, Pasquie, J, Billon, O, Roberts, J, Jesel, L, Borggrefe, M, Lambiase, P, Mansourati, J, Loeys, B, Leenhardt, A, Guicheney, P, Maury, P, Schulze-Bahr, E, Robyns, T, Breckpot, J, Babuty, D, Priori, S, Napolitano, C, Referral Center for inherited cardiac arrhythmia, N, de Asmundis, C, Brugada, P, Brugada, R, Arbelo, E, Brugada, J, Mabo, P, Behar, N, Giustetto, C, Sabater Molina, M, Gimeno, J, Hasdemir, C, Schwartz, P, Crotti, L, Mckeown, P, Sharma, S, Behr, E, Haissaguerre, M, Sacher, F, Rooryck, C, Tan, H, Remme, C, Postema, P, Delmar, M, Ellinor, P, Lubitz, S, Gourraud, J, Tanck, M, L. George Jr., A, Macrae, C, Burridge, P, Dina, C, Probst, V, Wilde, A, Schott, J, Redon &amp, R, Bezzina, C, Cardiology, Graduate School, Medical Biology, ACS - Amsterdam Cardiovascular Sciences, ACS - Heart failure & arrhythmias, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, APH - Methodology, Epidemiology and Data Science, MUMC+: DA KG Polikliniek (9), RS: Carim - H02 Cardiomyopathy, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H04 Arrhythmogenesis and cardiogenetics, and Cardiovascular Centre (CVC)

Subjects
EXPRESSION, [SDV]Life Sciences [q-bio], DIAGNOSIS, GUIDELINES, ANNOTATION, Article, NAV1.5 Voltage-Gated Sodium Channel, Young Adult, MANAGEMENT, Genetics, GWAS, Humans, Genetic Predisposition to Disease, 610 Medicine & health, SCN5A, Alleles, Brugada Syndrome, Allele, [SDV.GEN]Life Sciences [q-bio]/Genetics, HERITABILITY, Microtubule-Associated Protein, Brugada Syndrome, GWAS, SNPs, COMMON VARIANTS, Mutation, Disease Susceptibility, Human medicine, ENRICHMENT, Microtubule-Associated Proteins, SNPs, Human, GENERATION, Genome-Wide Association Study
Abstract

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na(V)1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na(V)1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings. Genome-wide association analyses identify new susceptibility loci for Brugada syndrome. Functional studies implicate microtubule-related trafficking effects on sodium channel expression as an underlying molecular mechanism., European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program [772376-EScORIAL]; Health~Holland; Top Sector Life Sciences Health; Wellcome Trust [076113, 085475, 090355]; Helmholtz Zentrum Munchen-German Research Center for Environmental Health - German Federal Ministry of Education and Research; State of Bavaria; Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ; research program Etoiles montantes des Pays de la Loire [REGIOCARD RPH081-U1087-REG-PDL]; ANR JCJC LEARN [R21006NN, RPV21014NNA]; H2020-MSCA-IF-2014 Program of the European Commission [RISTRAD-661617]; Canadian Heart Rhythm Society's George Mines Award; European Society of Cardiology research award; Philippa and Marvin Carsley Cardiology Chair; Fondation Leducq; National Institutes of Health (NIH) NHGRI T32 [1T32HG010464-01]; IRP-VERACITIES-New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES an I-SITE NExT health and engineering initiative (Ecole Centrale); IRP-VERACITIES-New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES an I-SITE NExT health and engineering initiative (Nantes University); IRP-GAINES-Genetic Architecture IN cardiovascular disEaSes - INSERM; CNRS; Amsterdam Cardiovascular Sciences fellowship; NHLBI BioData Catalyst Fellows Program; Dutch Heart Foundation [CVON PREDICT2]; Innovational Research Incentives Scheme Vidi grant from the Netherlands Organisation for Health Research and Development (ZonMw) [91714371]; Robert Lancaster Memorial Fund; Cardiac Risk in the Young; Wetenschappelijk Fonds Willy Gepts VUB-UZ Brussel; VUB IRP project `IMAGica: an Integrative personalized Medical Approach for Genetic diseases, Inherited Cardia Arrhythmias as a model' and Innoviris BRIDGE 2017; project `IGenCare: Integrated Personalised Medical Genomics Care Solution for Patients with Rare Genetic Diseases'; Barts BRC; DZHK (German Centre for Cardiovascular Research); BMBF (German Ministry of Education and Research); Danish Heart Foundation; IWT [140935]; ALS Liga Belgie; National Lottery of Belgium; KU Leuven Opening the Future Fund; HYPERGENES [HEALTH-F4-2007]; Leducq Foundation for Cardiovascular Research grant [18CVD05]; Netherlands CardioVascular Research Initiative [CVON PREDICT2]; NIH [HL47678, HL138103, 1RO1HL092577, R01HL128914, K24HL105780]; W.W. Smith Charitable Trust; Wistar Morris Fund; GOA-Antigone [33933]; Senior Clinical Fellowship of the Flemish Science Foundation (FWO); British Heart Foundation; BHF Clinical Research Training Fellowship [FS/11/71/28918]; Cardiac Risk in the Young and Robert Lancaster Memorial fund - McColl's Ltd. Retail Group; European Union's Horizon 2020 research and innovation program under acronym ESCAPE-NET [733381]; Dutch Heart Foundation; Fondation Leducq [14CVD01, 17CVD02]; American Heart Association [18SFRN34110082, 18SFRN34250007]; Bayer AG; NIH grant [1R01HL139731]; Federation Francaise de Cardiologie (PREVENT project); Leducq Foundation; Burroughs Wellecome Fund; Fondation pour la Recherche Medicale [DEQ20140329545]; National Agency for Research [ANR-GENSUD-14-CE10-0001]; Netherlands Organization for Scientific Research (VICI fellowship) [016.150.610]; [K23HL127704]; [R01 HL149826]; [P50 GM115305]; [NIH-RO1 HL134328], We are greatly indebted to the patients included in the study. We thank V. Cotard, C. Goutsmedt, M.-F. Le Cunff and N. Bourgeais for assistance in patient recruitment and L. Beekman for his technical support. We thank the biological resource centre for biobanking (CHU Nantes, Nantes Universite, Centre de ressources biologiques (BB0033-00040), F-44000 Nantes, France) for applying the following guidelines68. We are most grateful to the Genomics and Bioinformatics Core Facility of Nantes (GenoBiRD, Biogenouest, IFB) for its technical support. This research has been conducted using the UK Biobank resource; we are grateful to UK Biobank participants. The MINE study (J.H.V.) has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 772376-EScORIAL). The collaboration project is cofunded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk.Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355. The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum Munchen-German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ. J. Barc is supported by the research program Etoiles montantes des Pays de la Loire REGIOCARD RPH081-U1087-REG-PDL, ANR JCJC LEARN (R21006NN, RPV21014NNA) and by the H2020-MSCA-IF-2014 Program of the European Commission (RISTRAD-661617). R.T. is supported by the Canadian Heart Rhythm Society's George Mines Award, the European Society of Cardiology research award, and the Philippa and Marvin Carsley Cardiology Chair. D.Y.C. is supported by Fondation Leducq and National Institutes of Health (NIH) NHGRI T32 (no. 1T32HG010464-01). M. Baudic was supported by IRP-VERACITIES-New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES, an I-SITE NExT health and engineering initiative (Ecole Centrale and Nantes University) and by the IRP-GAINES-Genetic Architecture IN cardiovascular disEaSes funded by INSERM and CNRS. R.W. is supported by an Amsterdam Cardiovascular Sciences fellowship. S.C. is supported by the NHLBI BioData Catalyst Fellows Program. C.A.R. is supported by Fondation Leducq, the Dutch Heart Foundation (CVON PREDICT2) and the Innovational Research Incentives Scheme Vidi grant from the Netherlands Organisation for Health Research and Development (ZonMw; 91714371). Y.D.W. is supported by the Robert Lancaster Memorial Fund. M.P. is supported by Cardiac Risk in the Young. S.V.D. is supported by Wetenschappelijk Fonds Willy Gepts VUB-UZ Brussel, project `Unravelling the molecular genetic pathways of Brugada Syndrome by cardiomics research', VUB IRP project `IMAGica: an Integrative personalized Medical Approach for Genetic diseases, Inherited Cardia Arrhythmias as a model' and Innoviris BRIDGE 2017, project `IGenCare: Integrated Personalised Medical Genomics Care Solution for Patients with Rare Genetic Diseases'. S.H. is supported by the Barts BRC. B.R.; is supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). B.G.W. is supported by the Danish Heart Foundation. M.B.S. is supported by K23HL127704. Project MinE Belgium was supported by a grant from IWT (no. 140935), the ALS Liga Belgie, the National Lottery of Belgium and the KU Leuven Opening the Future Fund. D.C. and C.L. are supported by HYPERGENES (HEALTH-F4-2007). D.R. is supported by R01 HL149826, P50 GM115305. P.J.S. acknowledges the support of Leducq Foundation for Cardiovascular Research grant 18CVD05. P.V.D. is supported by the Netherlands CardioVascular Research Initiative (CVON PREDICT2). C.A. is supported by NIH HL47678 and HL138103, W.W. Smith Charitable Trust and Wistar Morris Fund. M.B. is Supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). P.D.L. is supported by UCL/UCLH Biomedicine NIHR and Barts BRC. B.L. is supported by GOA-Antigone 33933. J.B. is supported by a Senior Clinical Fellowship of the Flemish Science Foundation (FWO). E.B. is supported by the British Heart Foundation including BHF Clinical Research Training Fellowship (FS/11/71/28918: Future diagnostic role and new genetic loci in SADS), Cardiac Risk in the Young and Robert Lancaster Memorial fund sponsored by McColl's Ltd. Retail Group. H.L.T. is supported by the European Union's Horizon 2020 research and innovation program under acronym ESCAPE-NET, registered under grant agreement no. 733381, and the Dutch Heart Foundation (CVON RESCUED and PREDICT2 projects). M.D. is supported by NIH-RO1 HL134328. P.T.E. was supported by the Fondation Leducq (14CVD01), the NIH (1RO1HL092577, R01HL128914, K24HL105780), the American Heart Association (18SFRN34110082) and by a research grant from Bayer AG to the Broad Institute. S.A.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. J.-B.G. received a grant from the Federation Francaise de Cardiologie (PREVENT project). A.L.G. is supported by the Fondation Leducq. C.A.M.R. is supported by the Leducq Foundation and Burroughs Wellecome Fund. A.A.W. is supported by the Dutch Heart Foundation (CVON PREDICT2 project). J.-J.S. is supported by the Fondation pour la Recherche Medicale (DEQ20140329545). R.R. and P.G. are supported by the National Agency for Research (ANR-GENSUD-14-CE10-0001). C.R.B. is supported by the Dutch Heart Foundation (CVON PREDICT2 project), the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610) and Fondation Leducq (17CVD02).

Published
2022
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243. Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls

Author

Charles Antzelevitch, Ahmad S. Amin, Bo Gregers Winkel, Dan M. Roden, Stefan Kääb, Jonathan R. Skinner, Seiko Ohno, Julien Barc, Birgit Stallmeyer, Carla Giustetto, Connie R. Bezzina, Francesco Mazzarotto, Tomas Robyns, Carlo Napolitano, Stellan Mörner, Doris Škorić-Milosavljević, Sven Dittmann, Kenichiro Yamagata, Sonia Van Dooren, Anniek Corveleyn, Carlo de Asmundis, Ramon Brugada, K Usuda, Yuji Tanaka, Sven Zumhagen, Tadashi Nakajima, Johan Saenen, Elijah R. Behr, Hector Barajas-Martinez, Stéphane Bézieau, Masao Yoshinaga, Georgia Sarquella-Brugada, Paul G.A. Volders, Juan R. Gimeno, Lia Crotti, Charlotte Glinge, Andrea Mazzanti, Ingrid P.C. Krapels, Nicola Whiffin, Sebastian Clauss, Yoshiaki Kaneko, James S. Ware, Minoru Horie, Keiko Shimamoto, Isabelle Denjoy, Pieter G. Postema, Christian Krijger, Takeshi Aiba, Masahiko Kurabayashi, Pyotr G. Platonov, Regina Sebastiano, Cristina Gil Ortuño, Annika Rydberg, Roddy Walsh, Michael J. Ackerman, Hideki Itoh, M. Benjamin Shoemaker, Can Hasdemir, Pascale Guicheney, J. Martijn Bos, Frederic Sacher, Takeru Makiyama, Julieta Lazarte, Maarten P. van den Berg, Dominique Babuty, David J. Tester, Silvia Castelletti, Jacques Mansourati, Antoine Leenhardt, Paul A. van der Zwaag, Sanjay Sharma, Elena Arbelo, Candan Celen, Pier D. Lambiase, Maria Christina Kotta, Johannes Steinfurt, Jean-Baptiste Gourraud, Pedro Brugada, Wataru Shimizu, Josep Brugada, Jørgen K. Kanters, Eline A. Nannenberg, Silvia G. Priori, Mary N. Sheppard, Richard Redon, Morten S. Olesen, Jeroen Breckpot, Britt M. Beckmann, Naomasa Makita, Martin Borggrefe, Rafik Tadros, Jean-Jacques Schott, Jacob Tfelt-Hansen, Steven A. Lubitz, Hatice Şahin, Najim Lahrouchi, Michael Papadakis, Daisuke Hazeki, Kenshi Hayashi, Oscar Campuzano, Katja E. Odening, Federica Dagradi, Eric Schulze-Bahr, Boris Rudic, Hiroki Kimoto, Vincent Probst, Jason D. Roberts, Raphaël P. Martins, Bart Loeys, Daniela F. Giachino, F. Kyndt, Kimie Ohkubo, Taisuke Ishikawa, Catarina Lundin, Lut Van Laer, Patrick T. Ellinor, Maria Sabater Molina, Peter J. Schwartz, Annika Winbo, Wellcome Trust, Rosetrees Trust, British Heart Foundation, Walsh, R, Lahrouchi, N, Tadros, R, Kyndt, F, Glinge, C, Postema, P, Amin, A, Nannenberg, E, Ware, J, Whiffin, N, Mazzarotto, F, Skoric-Milosavljevic, D, Krijger, C, Arbelo, E, Babuty, D, Barajas-Martinez, H, Beckmann, B, Bezieau, S, Bos, J, Breckpot, J, Campuzano, O, Castelletti, S, Celen, C, Clauss, S, Corveleyn, A, Crotti, L, Dagradi, F, de Asmundis, C, Denjoy, I, Dittmann, S, Ellinor, P, Ortuno, C, Giustetto, C, Gourraud, J, Hazeki, D, Horie, M, Ishikawa, T, Itoh, H, Kaneko, Y, Kanters, J, Kimoto, H, Kotta, M, Krapels, I, Kurabayashi, M, Lazarte, J, Leenhardt, A, Loeys, B, Lundin, C, Makiyama, T, Mansourati, J, Martins, R, Mazzanti, A, Morner, S, Napolitano, C, Ohkubo, K, Papadakis, M, Rudic, B, Molina, M, Sacher, F, Sahin, H, Sarquella-Brugada, G, Sebastiano, R, Sharma, S, Sheppard, M, Shimamoto, K, Shoemaker, M, Stallmeyer, B, Steinfurt, J, Tanaka, Y, Tester, D, Usuda, K, van der Zwaag, P, Van Dooren, S, Van Laer, L, Winbo, A, Winkel, B, Yamagata, K, Zumhagen, S, Volders, P, Lubitz, S, Antzelevitch, C, Platonov, P, Odening, K, Roden, D, Roberts, J, Skinner, J, Tfelt-Hansen, J, van den Berg, M, Olesen, M, Lambiase, P, Borggrefe, M, Hayashi, K, Rydberg, A, Nakajima, T, Yoshinaga, M, Saenen, J, Kaab, S, Brugada, P, Robyns, T, Giachino, D, Ackerman, M, Brugada, R, Brugada, J, Gimeno, J, Hasdemir, C, Guicheney, P, Priori, S, Schulze-Bahr, E, Makita, N, Schwartz, P, Shimizu, W, Aiba, T, Schott, J, Redon, R, Ohno, S, Probst, V, Arnaout, A, Amelot, M, Anselme, F, Billon, O, Defaye, P, Dupuis, J, Jesel, L, Laurent, G, Maury, P, Pasquie, J, Wiart, F, Behr, E, Barc, J, Bezzina, C, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Pontchaillou [Rennes], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Ege Üniversitesi, Cardiovascular Centre (CVC), Nantes Referral Ctr Inherited Car, Cardiology, Graduate School, ACS - Heart failure & arrhythmias, Human Genetics, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, MUMC+: DA KG Polikliniek (9), RS: Carim - H02 Cardiomyopathy, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H04 Arrhythmogenesis and cardiogenetics, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Clinical sciences, Heartrhythmmanagement, Medical Genetics, Reproduction and Genetics, and Cardio-vascular diseases

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Nantes Referral Center for inherited cardiac arrhythmia, Disease, Arrhythmias, 030105 genetics & heredity, ACMG/AMP guidelines, Brugada, LQTS, variant interpretation, Medicine, Genetics (clinical), Brugada Syndrome, Brugada syndrome, Genetics, Genetics & Heredity, education.field_of_study, medicine.diagnostic_test, Molecular pathology, 3. Good health, Long QT Syndrome, Medical genetics, Population Control, Cardiology and Cardiovascular Medicine, Cardiac, Medical Genetics, Life Sciences & Biomedicine, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Long QT syndrome, Population, 610 Medicine & health, BIO/18 - GENETICA, Article, 03 medical and health sciences, Humans, Genetic Testing, cardiovascular diseases, education, Medicinsk genetik, Genetic testing, 0604 Genetics, Science & Technology, business.industry, Genetic heterogeneity, MUTATIONS, ACMG/AMP guideline, Arrhythmias, Cardiac, 1103 Clinical Sciences, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, medicine.disease, Mutation, 030104 developmental biology, Human medicine, business
Abstract

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing., Amsterdam Cardiovascular Sciences fellowship; Dutch Heart Foundation (CVON Predict-2/Concor-genes); Netherlands Organization for Scientific ResearchNetherlands Organization for Scientific Research (NWO) [VICI 016.150.610]; Fondation LeducqLeducq Foundation, R.W. is supported by an Amsterdam Cardiovascular Sciences fellowship. C.R.B. is supported by the Dutch Heart Foundation (CVON Predict-2/Concor-genes), Netherlands Organization for Scientific Research (VICI 016.150.610), and Fondation Leducq. See Supplement for all Acknowledgements.

Published
2020
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244. Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome

Author

Yvonne M. Hoedemaekers, M. Ben Shoemaker, Pascale Guicheney, Antoine Leenhardt, Andrea Mazzanti, Minoru Horie, Jan H. Veldink, Isabelle Denjoy, Yu Kucho, Chiea Chuen Khor, Tomas Robyns, Carlo Napolitano, Peter Weeke, J. Martijn Bos, David J. Tester, Hanno L. Tan, Annika Rydberg, Patrick T. Ellinor, Pilar Galan, Taisuke Ishikawa, Seiko Ohno, Peter J. Schwartz, Masao Yoshinaga, Thomas Werge, Marta Ribasés, Bart Loeys, Jean-Jacques Schott, Jacob Tfelt-Hansen, Ulla-Britt Diamant, Marko Ernsting, Georgia Sarquella-Brugada, Yuka Mizusawa, Michael Christiansen, Pyotr G. Platonov, Annika Winbo, Thomas Meitinger, Keiko Shimamoto, Cristina Barlassina, Pieter G. Postema, Takeru Makiyama, Maarten P. van den Berg, Yanushi D. Wijeyeratne, Wataru Shimizu, Charles Antzelevitch, Christopher Newton-Cheh, Martina Müller-Nurasyid, Dan M. Roden, Vincent Probst, Takeshi Aiba, Lia Crotti, Daniele Cusi, Britt M. Beckmann, Johan Saenen, Peter Lichtner, Oscar Campuzano, Tin Aung, Nynke Hofman, Morten S. Olesen, Matteo Pedrazzini, Elijah R. Behr, Karen E. Morrison, Najim Lahrouchi, Katja E. Odening, Andrew D. Krahn, Kari L. Turkowski, J. Peter van Tintelen, Steven A. Lubitz, Federica Dagradi, Josep Brugada, Julien Barc, Birgit Stallmeyer, Stefan Kääb, Sven Zumhagen, Jonathan R. Skinner, Michael W.T. Tanck, Christopher Shaw, Brianna Davies, Eric Schulze-Bahr, Mineo Ozaki, Roddy Walsh, Antoine Andorin, Leonard H. van den Berg, Silvia G. Priori, Johannes Steinfurt, Jean-Baptiste Gourraud, Eline A. Nannenberg, Mark Lathrop, Rafik Tadros, Ramon Brugada, Leander Beekman, Peter M. Andersen, Ryan Pfeiffer, Boris Rudic, Reza Jabbari, Kanae Hasegawa, Jeroen Breckpot, Naomasa Makita, Michael J. Ackerman, Arthur A.M. Wilde, Hideki Itoh, Martin Borggrefe, Elena Arbelo, Connie R. Bezzina, Pamela J. Shaw, Ammar Al-Chalabi, Markus Munter, Cardiology, Graduate School, ACS - Heart failure & arrhythmias, ACS - Amsterdam Cardiovascular Sciences, Human Genetics, Epidemiology and Data Science, APH - Methodology, ACS - Atherosclerosis & ischemic syndromes, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences. Amsterdam University Medical Center, University of Amsterdam, European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart (ERN GUARD-Heart), Institut de Cardiologie de Montreal, Université de Montréal (UdeM), Istituto Auxologico Italiano, Shiga University of Medical Science, University of Fukui [Bunkyo], Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Lahrouchi, N, Tadros, R, Crotti, L, Mizusawa, Y, Postema, P, Beekman, L, Walsh, R, Hasegawa, K, Barc, J, Ernsting, M, Turkowski, K, Mazzanti, A, Beckmann, B, Shimamoto, K, Diamant, U, Wijeyeratne, Y, Kucho, Y, Robyns, T, Ishikawa, T, Arbelo, E, Christiansen, M, Winbo, A, Jabbari, R, Lubitz, S, Steinfurt, J, Rudic, B, Loeys, B, Shoemaker, M, Weeke, P, Pfeiffer, R, Davies, B, Andorin, A, Hofman, N, Dagradi, F, Pedrazzini, M, Tester, D, Bos, J, Sarquella-Brugada, G, Campuzano, Ó, Platonov, P, Stallmeyer, B, Zumhagen, S, Nannenberg, E, Veldink, J, van den Berg, L, Al-Chalabi, A, Shaw, C, Shaw, P, Morrison, K, Andersen, P, Müller-Nurasyid, M, Cusi, D, Barlassina, C, Galan, P, Lathrop, M, Munter, M, Werge, T, Ribasés, M, Aung, T, Khor, C, Ozaki, M, Lichtner, P, Meitinger, T, van Tintelen, J, Hoedemaekers, Y, Denjoy, I, Leenhardt, A, Napolitano, C, Shimizu, W, Schott, J, Gourraud, J, Makiyama, T, Ohno, S, Itoh, H, Krahn, A, Antzelevitch, C, Roden, D, Saenen, J, Borggrefe, M, Odening, K, Ellinor, P, Tfelt-Hansen, J, Skinner, J, van den Berg, M, Olesen, M, Brugada, J, Brugada, R, Makita, N, Breckpot, J, Yoshinaga, M, Behr, E, Rydberg, A, Aiba, T, Kääb, S, Priori, S, Guicheney, P, Tan, H, Newton-Cheh, C, Ackerman, M, Schwartz, P, Schulze-Bahr, E, Probst, V, Horie, M, Wilde, A, Tanck, M, Bezzina, C, and Cardiovascular Centre (CVC)

Subjects
Multifactorial Inheritance, [SDV]Life Sciences [q-bio], Genome-wide association study, 030204 cardiovascular system & hematology, Severity of Illness Index, Sudden cardiac death, Electrocardiography, 0302 clinical medicine, inheritance pattern, Medicine, Cardiac and Cardiovascular Systems, Age of Onset, Genetics, 0303 health sciences, Kardiologi, Genetic disorder, genome-wide association study, Prognosis, 3. Good health, Phenotype, Medical genetics, Cardiology and Cardiovascular Medicine, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Genotype, Long QT syndrome, 610 Medicine & health, BIO/18 - GENETICA, QT interval, Polymorphism, Single Nucleotide, 03 medical and health sciences, Young Adult, Physiology (medical), long QT syndrome, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Alleles, Genetic Association Studies, MED/01 - STATISTICA MEDICA, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, inheritance patterns, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, Heritability, medicine.disease, Genetic architecture, Genome-wide Association Study, Inheritance Patterns, Long Qt Syndrome, Case-Control Studies, Human medicine, business
Abstract

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance ( P −8 ) near NOS1AP , KCNQ1 , and KLF12 , and 1 missense variant in KCNE1 (p.Asp85Asn) at the suggestive threshold ( P −6 ). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r g =0.40; P =3.2×10 −3 ). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls ( P P Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.

Published
2020
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245. Use of the prophylactic implantable cardioverter defibrillator for patients with normal hearts.

Author

Brugada, Pedro, Brugada, Ramon, Brugada, P, Brugada, R, Brugada, J, and Geelen, P

Subjects
*IMPLANTABLE cardioverter-defibrillators, *VENTRICULAR fibrillation, *PREVENTION, *LONG QT syndrome treatment, *BUNDLE-branch block, *CARDIAC arrest, *LONG QT syndrome, *VENTRICULAR tachycardia, *THERAPEUTICS, CARDIAC arrest prevention
Abstract

About 10-20% of patients dying suddenly and unexpectedly do not have structural heart disease. The major causes of sudden death in this population are acute ischemia, the syndrome of right bundle branch block, and ST-elevation from V1 to V3, the long QT-syndrome, and the Wolff-Parkinson-While syndrome. In some patients, none of these syndromes can be recognized and ventricular fibrillation is classified as idiopathic. There are good preventive and therapeutic methods against acute ischemia and there are also curative treatments for the Wolff-Parkinson-White syndrome. Patients with idiopathic ventricular fibrillation cannot be recognized beforehand. However, there are electrocardiographic and genetic markers for the Brugada syndrome and the long QT syndrome. It is, therefore, justified to discuss the possible role of the prophylactic defibrillator to prevent sudden death in these 2 syndromes for which no effective treatment exists. Patients with Brugada syndrome have a high incidence of sudden death, and prophylactic defibrillators are indicated in patients with inducible arrhythmias at electrophysiologic study, irrespective of symptoms. On the contrary, the incidence of sudden death in the long QT syndrome is very low, making prophylactic defibrillator implantation not cost-effective. [ABSTRACT FROM AUTHOR]

Published
1999
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246. Loss-of-function KCNH2 mutation in a family with long QT syndrome, epilepsy, and sudden death

Author

Cestèle, Sandrine, Partemi, Sara, Cestele, Sandrine, Pezzella, Marianna, Campuzano, Oscar, Paravidino, Roberta, Pascali, Vincenzo, Zara, Federico, Tassinari, Carlo Alberto, Striano, Salvatore, Oliva, Antonio, Brugada, Ramon, Mantegazza, Massimo, Striano, Pasquale, Université Côte d'Azur, CNRS, UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Institute of Legal Medicine, Catholic University, Ingénierie des protéines (IP), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Pediatric Neurology and Neuromuscular Diseases Unit, Universita degli studi di Genova, Cardiovascular Genetics Center, Universitat de Girona (UdG), Institute G. Gaslini, Department of Neurological Sciences, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Epilepsy Center, Università degli studi di Napoli Federico II, departament de Quimica, Universitat Autònoma de Barcelona (UAB), Department of Neurophysiopathology, Besta Neurological Institute, Partemi, S, Cest?le, S, Pezzella, M, Campuzano, O, Paravidino, R, Pascali, Vl, Zara, F, Tassinari, Ca, Striano, Salvatore, Oliva, A, Brugada, R, Mantegazza, M, Striano, Pasquale, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), IRCCS, Università degli studi di Genova = University of Genoa (UniGe), and University of Naples Federico II = Università degli studi di Napoli Federico II

Subjects
ERG1 Potassium Channel, Patch-Clamp Techniques, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Twins, 030204 cardiovascular system & hematology, Membrane Potentials, Epilepsy, Death, Sudden, Electrocardiography, 0302 clinical medicine, Channelopathy, Twins, Dizygotic, KCNH2, ComputingMilieux_MISCELLANEOUS, Cell Line, Transformed, medicine.diagnostic_test, Sudden death, Death, Long QT Syndrome, Neurology, Mutation (genetic algorithm), Cardiology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Adolescent, Long QT syndrome, Transfection, Biophysical Phenomena, Cell Line, 03 medical and health sciences, Bacterial Proteins, Internal medicine, medicine, Dizygotic, Humans, Point Mutation, cardiovascular diseases, Loss function, Family Health, business.industry, Point mutation, Settore MED/43 - MEDICINA LEGALE, medicine.disease, Sudden, Electric Stimulation, Ether-A-Go-Go Potassium Channels, Luminescent Proteins, Endocrinology, Transformed, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

International audience; There has been increased interest in a possible association between epilepsy channelopathies and cardiac arrhythmias, such as long QT syndrome (LQTS). We report a kindred that features LQTS, idiopathic epilepsy, and increased risk of sudden death. Genetic study showed a previously unreported heterozygous point mutation (c.246T>C) in the KCNH2 gene. Functional studies showed that the mutation induces severe loss of function. This observation provides further evidence for a possible link between idiopathic epilepsy and LQTS.

Published
2013
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247. Genetic fate mapping identifies second heart field progenitor cells as a source of adipocytes in arrhythmogenic right ventricular cardiomyopathy

Author

Ramon Brugada, James T. Willerson, Achim Bell, Tack Ki Leung, Robert J. Schwartz, Raffaella Lombardi, Jinjiang Dong, Ali J. Marian, Gabriela Rodriguez, Lombardi, R., Dong, J., Rodriguez, G., Bell, A., Leung, T. K., Schwartz, R. J., Willerson, J. T., Brugada, R., and Marian, A. J.

Subjects
Physiology, Fibrosi, Transcription Factor, Bone Morphogenetic Protein 7, Wnt Protein, Mice, Adipocytes, TCF Transcription Factor, MEF2 Transcription Factor, MEF2C, Arrhythmogenic Right Ventricular Dysplasia, Adipogenesis, Adipocyte, biology, MEF2 Transcription Factors, MADS Domain Protein, Stem Cells, Wnt signaling pathway, Desmosome, Homeodomain Protein, Echocardiography, Doppler, Arrhythmogenic right ventricular dysplasia, Cell biology, Phenotype, Myogenic Regulatory Factors, Progenitor cell, Homeobox Protein Nkx-2.5, TCF Transcription Factors, Cardiology and Cardiovascular Medicine, Transcription Factor 7-Like 2 Protein, Human, Signal Transduction, Adult, medicine.medical_specialty, Myogenic Regulatory Factor, Genotype, LIM-Homeodomain Proteins, Plakoglobin, MADS Domain Proteins, Heart failure, Mice, Transgenic, LIM-Homeodomain Protein, Article, Right ventricular cardiomyopathy, Stem Cell, Internal medicine, medicine, Animals, Humans, Cell Lineage, Homeodomain Proteins, Adipogenesi, Myosin Heavy Chains, Desmoplakin, Animal, Myocardium, Myosin Heavy Chain, medicine.disease, Fibrosis, Wnt signaling, Wnt Proteins, Disease Models, Animal, Endocrinology, Desmoplakins, biology.protein, ISL1, gamma Catenin, Transcription Factors
Abstract

The phenotypic hallmark of arrhythmogenic right ventricular cardiomyopathy, a genetic disease of desmosomal proteins, is fibroadipocytic replacement of the right ventricle. Cellular origin of excess adipocytes, the responsible mechanism(s) and the basis for predominant involvement of the right ventricle are unknown. We generated 3 sets of lineage tracer mice regulated by cardiac lineage promoters α-myosin heavy chain (αMyHC), Nkx2.5, or Mef2C. We conditionally expressed the reporter enhanced yellow fluorescent protein while concomitantly deleting the desmosomal protein desmoplakin in cardiac myocyte lineages using the Cre-LoxP technique. Lineage tracer mice showed excess fibroadiposis and increased numbers of adipocytes in the hearts. Few adipocytes in the hearts of αMyHC-regulated lineage tracer mice, but the majority of adipocytes in the hearts of Nkx2.5- and Mef2C-regulated lineage tracer mice, expressed enhanced yellow fluorescent protein. In addition, rare cells coexpressed adipogenic transcription factors and the second heart field markers Isl1 and Mef2C in the lineage tracer mouse hearts and in human myocardium from patients with arrhythmogenic right ventricular cardiomyopathy. To delineate the responsible mechanism, we generated transgenic mice expressing desmosomal protein plakoglobin in myocyte lineages. Transgene plakoglobin translocated to nucleus, detected by immunoblotting and immunofluorescence staining and coimmunoprecipitated with Tcf7l2, a canonical Wnt signaling transcription factor. Expression levels of canonical Wnt/Tcf7l2 targets bone morphogenetic protein 7 and Wnt5b, which promote adipogenesis, were increased and expression level of connective tissue growth factor, an inhibitor of adipogenesis, was decreased. We conclude adipocytes in arrhythmogenic right ventricular cardiomyopathy originate from the second heart field cardiac progenitors, which switch to an adipogenic fate because of suppressed canonical Wnt signaling by nuclear plakoglobin. © 2009 American Heart Association, Inc.

Published
2009

248. Investigating cardiac genetic background in sudden infant death syndrome (SIDS).

Author

Cazzato F, Coll M, Grassi S, Fernàndez-Falgueras A, Nogué-Navarro L, Iglesias A, Castellà J, Oliva A, and Brugada R

Subjects
Humans, Male, Infant, Female, Infant, Newborn, Myosin Heavy Chains genetics, Cell Cycle Proteins genetics, Genetic Variation, Genetic Testing, Transcription Factors genetics, Mutation, Organic Anion Transporters genetics, Connectin, Sudden Infant Death genetics, NAV1.5 Voltage-Gated Sodium Channel genetics, High-Throughput Nucleotide Sequencing
Abstract

Sudden infant death syndrome (SIDS) is still the leading cause of death for newborns in developed countries. The pathophysiological mechanisms have not been fully clarified, but in some of SIDS cases variants of genes associated with inherited cardiac conditions are found. In this study, an analysis of SCD-related genes was performed to determine the prevalence of rare pathogenic (P) or likely pathogenic (LP) variants that could provide an unambiguous explanation for the fatal event. A cohort of 76 SIDS cases underwent Next-Generation Sequencing (NGS) analysis with a custom panel of SCD-related genes. Rare variants were classified according to the guidelines provided by the American College of Medical Genetics and Genomics (ACMG) and the specifications of the ClinGen association. Post-mortem genetic testing identified 50 (65.8%) carriers of at least one variant in SCD genes. 104 rare genetic variants were found, 65.4% in genes encoding structural proteins. Only 4 out of 76 cases (5.3%) hosted at least a P or LP variant found in genes with structural or structural/arrhythmogenic functions (SLC22A5, SCN5A, MYL3and TTN). 99 variants were classified as of uncertain significance (VUS). The difference in the distribution of variants between gene groups by function was not statistically significant (chi square, p = 0,219). Despite this, most of the variants concerned structural genes that were supposed to have a close interaction with ion channels, thus providing an explanation for the arrhythmic event. Segregation analysis, reclassification of VUS variants and identification of new associated genes could clarify the implications of the current findings., (© 2024. The Author(s).)

Published
2024
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249. Novel risk loci for COVID-19 hospitalization among admixed American populations.

Author

Diz-de Almeida S, Cruz R, Luchessi AD, Lorenzo-Salazar JM, de Heredia ML, Quintela I, González-Montelongo R, Nogueira Silbiger V, Porras MS, Tenorio Castaño JA, Nevado J, Aguado JM, Aguilar C, Aguilera-Albesa S, Almadana V, Almoguera B, Alvarez N, Andreu-Bernabeu Á, Arana-Arri E, Arango C, Arranz MJ, Artiga MJ, Baptista-Rosas RC, Barreda-Sánchez M, Belhassen-Garcia M, Bezerra JF, Bezerra MAC, Boix-Palop L, Brion M, Brugada R, Bustos M, Calderón EJ, Carbonell C, Castano L, Castelao JE, Conde-Vicente R, Cordero-Lorenzana ML, Cortes-Sanchez JL, Corton M, Darnaude MT, De Martino-Rodríguez A, Del Campo-Pérez V, de Bustamante AD, Domínguez-Garrido E, Eirós R, Fariñas MC, Fernandez-Nestosa MJ, Fernández-Robelo U, Fernández-Rodríguez A, Fernández-Villa T, Gago-Dominguez M, Gil-Fournier B, Gómez-Arrue J, Álvarez BG, Bernaldo de Quirós FG, González-Neira A, González-Peñas J, Gutiérrez-Bautista JF, Herrero MJ, Herrero-Gonzalez A, Jimenez-Sousa MA, Lattig MC, Borja AL, Lopez-Rodriguez R, Mancebo E, Martín-López C, Martín V, Martinez-Nieto O, Martinez-Lopez I, Martinez-Resendez MF, Martinez-Perez A, Mazzeu JF, Macías EM, Minguez P, Cuerda VM, Oliveira SF, Ortega-Paino E, Parellada M, Paz-Artal E, Santos NPC, Pérez-Matute P, Perez P, Pérez-Tomás ME, Perucho T, Pinsach-Abuin M, Pita G, Pompa-Mera EN, Porras-Hurtado GL, Pujol A, León SR, Resino S, Fernandes MR, Rodríguez-Ruiz E, Rodriguez-Artalejo F, Rodriguez-Garcia JA, Ruiz-Cabello F, Ruiz-Hornillos J, Ryan P, Soria JM, Souto JC, Tamayo E, Tamayo-Velasco A, Taracido-Fernandez JC, Teper A, Torres-Tobar L, Urioste M, Valencia-Ramos J, Yáñez Z, Zarate R, de Rojas I, Ruiz A, Sánchez P, Real LM, Guillen-Navarro E, Ayuso C, Parra E, Riancho JA, Rojas-Martinez A, Flores C, Lapunzina P, and Carracedo Á

Subjects
Humans, SARS-CoV-2 genetics, Female, Male, Genetic Loci, Risk Factors, Polymorphism, Single Nucleotide, Middle Aged, Aged, Latin America epidemiology, COVID-19 genetics, COVID-19 epidemiology, Genome-Wide Association Study, Hospitalization statistics & numerical data, Genetic Predisposition to Disease
Abstract

The genetic basis of severe COVID-19 has been thoroughly studied, and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we conducted a genome-wide association study (GWAS) for COVID-19 hospitalization in admixed Americans, comprising a total of 4702 hospitalized cases recruited by SCOURGE and seven other participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and were first discovered in Latin American populations ( BAZ2B and DDIAS ). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in CREBBP . Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort. This study constitutes the largest GWAS for COVID-19 hospitalization in admixed Latin Americans conducted to date. This allowed to reveal novel risk loci and emphasize the need of considering the diversity of populations in genomic research., Competing Interests: SD, RC, AL, JL, Md, IQ, RG, VN, MP, JT, JN, JA, CA, SA, VA, BA, NA, ÁA, EA, CA, MA, MA, RB, MB, MB, JB, MB, LB, MB, RB, MB, EC, CC, LC, JC, RC, MC, JC, MC, MD, AD, Vd, Ad, ED, RE, MF, MF, UF, AF, TF, MG, BG, JG, BÁ, FB, AG, JG, JG, MH, AH, MJ, ML, AB, RL, EM, CM, VM, OM, IM, MM, AM, JM, EM, PM, VC, SO, EO, MP, EP, NS, PP, PP, MP, TP, MP, GP, EP, GP, AP, SL, SR, MF, ER, FR, JR, FR, JR, PR, JS, JS, ET, AT, JT, AT, LT, MU, JV, ZY, RZ, Id, AR, PS, LR, EG, CA, EP, JR, AR, CF, PL, ÁC No competing interests declared, (© 2024, Diz-de Almeida, Cruz et al.)

Published
2024
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250. An international multicenter cohort study on implantable cardioverter-defibrillators for the treatment of symptomatic children with catecholaminergic polymorphic ventricular tachycardia.

Author

Lamba A, Roston TM, Peltenburg PJ, Kallas D, Franciosi S, Lieve KVV, Kannankeril PJ, Horie M, Ohno S, Brugada R, Aiba T, Fischbach P, Knight L, Till J, Kwok SY, Probst V, Backhoff D, LaPage MJ, Batra AS, Drago F, Haugaa K, Krahn AD, Robyns T, Swan H, Tavacova T, van der Werf C, Atallah J, Borggrefe M, Rudic B, Sarquella-Brugada G, Chorin E, Hill A, Kammeraad J, Kamp A, Law I, Perry J, Roberts JD, Tisma-Dupanovic S, Semsarian C, Skinner JR, Tfelt-Hansen J, Denjoy I, Leenhardt A, Schwartz PJ, Ackerman MJ, Blom NA, Wilde AAM, and Sanatani S

Subjects
Humans, Male, Female, Child, Adolescent, Ryanodine Receptor Calcium Release Channel genetics, Follow-Up Studies, Child, Preschool, Retrospective Studies, Treatment Outcome, Defibrillators, Implantable, Tachycardia, Ventricular therapy, Tachycardia, Ventricular physiopathology, Death, Sudden, Cardiac prevention & control, Death, Sudden, Cardiac etiology
Abstract

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) may cause sudden cardiac death (SCD) despite medical therapy. Therefore, implantable cardioverter-defibrillators (ICDs) are commonly advised. However, there is limited data on the outcomes of ICD use in children., Objective: The purpose of this study was to compare the risk of arrhythmic events in pediatric patients with CPVT with and without an ICD., Methods: We compared the risk of SCD in patients with RYR2 (ryanodine receptor 2) variants and phenotype-positive symptomatic CPVT patients with and without an ICD who were younger than 19 years and had no history of sudden cardiac arrest at phenotype diagnosis. The primary outcome was SCD; secondary outcomes were composite end points of SCD, sudden cardiac arrest, or appropriate ICD shocks with or without arrhythmic syncope., Results: The study included 235 patients, 73 with an ICD (31.1%) and 162 without an ICD (68.9%). Over a median follow-up of 8.0 years (interquartile range 4.3-13.4 years), SCD occurred in 7 patients (3.0%), of whom 4 (57.1%) were noncompliant with medications and none had an ICD. Patients with ICD had a higher risk of both secondary composite outcomes (without syncope: hazard ratio 5.85; 95% confidence interval 3.40-10.09; P < .0001; with syncope: hazard ratio 2.55; 95% confidence interval 1.50-4.34; P = .0005). Thirty-one patients with ICD (42.5%) experienced appropriate shocks, 18 (24.7%) inappropriate shocks, and 21 (28.8%) device-related complications., Conclusion: SCD events occurred only in patients without an ICD and mostly in those not on optimal medical therapy. Patients with an ICD had a high risk of appropriate and inappropriate shocks, which may be reduced with appropriate device programming. Severe ICD complications were common, and risks vs benefits of ICDs need to be considered., Competing Interests: Disclosures All authors have no conflicts to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Published
2024
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