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7 results on '"Rudic, B"'

1. Genetic analysis identifies the SLC4A3 anion exchanger as a major gene for short QT syndrome.

Author

Christiansen MK, Kjær-Sørensen K, Clavsen NC, Dittmann S, Jensen MF, Guldbrandsen HØ, Pedersen LN, Sørensen RH, Lildballe DL, Müller K, Müller P, Vogel K, Rudic B, Borggrefe M, Oxvig C, Aalkjær C, Schulze-Bahr E, Matchkov V, Bundgaard H, and Jensen HK

Subjects
Animals, Humans, Arrhythmias, Cardiac, Death, Sudden, Cardiac prevention & control, Electrocardiography methods, Zebrafish
Abstract

Background: A variant in the SLC4A3 anion exchanger has been identified as a novel cause of short QT syndrome (SQTS), but the clinical importance of SLC4A3 as a cause of SQTS or sudden cardiac death remains unknown., Objective: The purpose of this study was to investigate the prevalence of potential disease-causing variants in SQTS patients using gene panels including SLC4A3., Methods: In this multicenter study, genetic testing was performed in 34 index patients with SQTS. The pathogenicity of novel SLC4A3variants was validated in a zebrafish embryo heart model., Results: Potentially disease-causing variants were identified in 9 (26%) patients and were mainly (15%) located in SLC4A3: 4 patients heterozygous for novel nonsynonymous SLC4A3 variants-p.Arg600Cys, p.Arg621Trp, p.Glu852Asp, and p.Arg952His-and 1 patient with the known p.Arg370His variant. In other SQTS genes, potentially disease-causing variants were less frequent (2× in KCNQ1, 1× in KCNJ2, and CACNA1C each). SLC4A3 variant carriers (n = 5) had a similar heart rate but shorter QT and J point to T wave peak intervals than did noncarriers (n = 29). Knockdown of slc4a3 in zebrafish resulted in shortened heart rate-corrected QT intervals (calculated using the Bazett formula) that could be rescued by overexpression of the native human SLC4A3-encoded protein (AE3), but neither by the mutated AE3 variants p.Arg600Cys, p.Arg621Trp, p.Glu852Asp nor by p.Arg952His, suggesting pathogenicity of these variants. Dysfunction in slc4a3/AE3 was associated with alkaline cytosol and shortened action potential of cardiomyocytes., Conclusion: In about a quarter of patients with SQTS, a potentially disease-causing variant can be identified. Nonsynonymous variants in SLC4A3 represent the most common cause of SQTS, underscoring the importance of including SLC4A3 in the genetic screening of patients with SQTS or sudden cardiac death., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Published
2023
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2. Long-term follow-up of implantable cardioverter-defibrillators in Short QT syndrome.

Author

El-Battrawy I, Besler J, Ansari U, Liebe V, Schimpf R, Tülümen E, Rudic B, Lang S, Odening K, Cyganek L, Wolpert C, Zhou X, Borggrefe M, and Akin I

Subjects
Arrhythmias, Cardiac physiopathology, Follow-Up Studies, Humans, Time Factors, Treatment Outcome, Arrhythmias, Cardiac therapy, Defibrillators, Implantable, Electrocardiography
Abstract

Background: Short QT syndrome (SQTS) is associated with sudden cardiac death and implantable cardioverter-defibrillator (ICD) implantation is recommended in this rare disease. However, only a few SQTS families have been reported in literature with limited follow-up data., Objectives: In the recent study, we describe the outcome data of 57 SQTS patients receiving ICD implantation. This includes seven SQTS families consecutively admitted to our hospital between 2002 and 2017 as well as patients reported in published literature., Methods: Seven SQTS patients admitted to our hospital were followed up. Additionally, 7 studies out of a total of 626 researched articles were identified through systematic database search (PubMed, Web of Science, Cochrane Library, and Cinahl) and their data analyzed according to our model., Results: Complications during a median follow-up time of 67.4 months (IQR 6-162 months) were documented in 31 (54%) patients. Inappropriate shocks were seen in 33% due to T wave oversensing (8.7%), supraventricular tachycardia (19%), lead failure and fracture (21%). Further complications were infection (10%), battery depletion (7%) and psychological distress (3.5%). Appropriate shocks were documented in 19%. Three patients (5%) were treated with s-ICD due to recurrent complications of transvenous ICD., Conclusion: ICD therapy is an effective therapy in SQTS patients. However, it is also associated with significant risk of device-related complications.

Published
2019
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3. Cardiac impact of R-wave triggered irreversible electroporation therapy.

Author

Kostrzewa M, Tueluemen E, Rudic B, Rathmann N, Akin I, Henzler T, Liebe V, Schoenberg SO, Borggrefe M, and Diehl SJ

Subjects
Arrhythmias, Cardiac epidemiology, Arrhythmias, Cardiac physiopathology, Electrochemotherapy methods, Female, Follow-Up Studies, Germany epidemiology, Humans, Incidence, Male, Middle Aged, Prospective Studies, Arrhythmias, Cardiac etiology, Electrocardiography, Electrochemotherapy adverse effects, Neoplasms drug therapy
Abstract

Background: Irreversible electroporation (IRE) is a novel tumor ablative therapy technique, using electric fields to induce apoptosis in target tissues. Whether these electric pulses of high field strength can cause cardiac damage and/or ablation-induced arrhythmias is unclear., Objective: The purpose of this study was to systematically evaluate the safety of electrocardiogram (ECG)-gated IRE with regard to cardiac side effects., Methods: In all patients, 12-lead ECG and signal-averaged ECG (SAECG) recordings were performed before and after IRE and 24-hour Holter recording on the day of the IRE procedure. Venous blood samples (N-terminal pro-brain-type natriuretic peptide [NT-proBNP], high-sensitive troponin I [hsTnI]) were obtained before and 4 and 16 hours after the procedure. Patients with abnormal findings were reevaluated after 3 months., Results: In total, 26 patients with an oncologic indication for IRE (11 females, mean age 62.9 years) were prospectively enrolled. Nine patients (34.6%) showed an increase in hsTnI and 21 patients (80.8%) an increase in NT-proBNP after ablation. Fifteen patients (57%) developed arrhythmias related to the procedure. One patient, in whom hsTnI and NT-proBNP had increased, developed multiple, nonsustained ventricular tachycardia events. In another patient, atrial fibrillation was triggered twice in 2 separate procedures. Twelve patients had clinically benign arrhythmias. SAECG was negative in all patients., Conclusion: Subclinical myocardial injury and nonfatal cardiac arrhythmias can occur in the context of IRE treatment. Although no sustained cardiac injuries could be found at 3-month follow-up, we propose implementation of a cardiac safety algorithm consisting of cardiac biomarkers and ECG monitoring when IRE is conducted., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Published
2018
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4. Subcutaneous implantable cardioverter-defibrillator: First single-center experience with other cardiac implantable electronic devices.

Author

Kuschyk J, Stach K, Tülümen E, Rudic B, Liebe V, Schimpf R, Borggrefe M, and Röger S

Subjects
Adult, Aged, Combined Modality Therapy, Defibrillators, Implantable, Female, Follow-Up Studies, Heart Failure diagnosis, Heart Failure mortality, Humans, Male, Middle Aged, Radiography, Thoracic, Retrospective Studies, Risk Assessment, Sampling Studies, Severity of Illness Index, Skin, Survival Rate, Tachycardia, Ventricular diagnosis, Tachycardia, Ventricular mortality, Treatment Outcome, Vagus Nerve Stimulation methods, Electrocardiography methods, Heart Failure therapy, Pacemaker, Artificial, Tachycardia, Ventricular therapy
Abstract

Background: The subcutaneous implantable cardioverter-defibrillator (S-ICD) is an implantable device for antiarrhythmic therapy with no intravascular leads., Objective: The purpose of this study was to describe the technical feasibility of combining the S-ICD with other cardiac implantable electronic devices (CIEDs), including pacemakers with transvenous or epicardial electrodes. We also provide the first experience of combining an S-ICD with catheter-based therapies, including cardiac contractility modulation (CCM) and vagus nerve stimulation., Methods: Between July 2011 and November 2014, 6 patients received a CCM device and S-ICD, 3 patients with a single-chamber pacemaker using either transvenous or epicardial pacing electrodes received and S-ICD, and 1 patient with an implanted S-ICD received vagus nerve stimulation. In all patients, intraoperative S-ICD testing, crosstalk tests, and postoperative ergometric testing were performed., Results: In all 10 patients, device implantations were successfully performed without complications. S-ICD therapy was shown to be technically feasible with concomitant CIED. Mean follow-up was nearly 17 months. S-ICD testing and crosstalk testing before and during exercise enabled device programming across a broad range of test conditions and was associated with no subsequent evidence of adverse device interaction. None of the devices required permanent inactivation or removal, and no patient received an inappropriate shock., Conclusion: In suitable patients, combining an S-ICD with CCM or pacemaker may provide an acceptable means to reduce the number of transvascular leads. S-ICD appeared safe with CCM over an intermediate follow-up period. Additional prospective randomized controlled trials examining S-ICD in conjunction with CIEDs are warranted., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Published
2015
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5. Early repolarization pattern is associated with ventricular fibrillation in patients with acute myocardial infarction.

Author

Rudic B, Veltmann C, Kuntz E, Behnes M, Elmas E, Konrad T, Kuschyk J, Weiss C, Borggrefe M, and Schimpf R

Subjects
Aged, Case-Control Studies, Electrophysiologic Techniques, Cardiac, Female, Humans, Male, Middle Aged, Electrocardiography, Heart Conduction System physiopathology, Myocardial Infarction complications, Myocardial Infarction physiopathology, Ventricular Fibrillation complications, Ventricular Fibrillation physiopathology
Abstract

Background: For years early repolarization (ER) has been considered as a benign electrocardiographic finding. However, recent reports show that ER is associated with a higher incidence of ventricular fibrillation (VF) and sudden cardiac death in patients without structural heart disease. Sporadic case studies have pointed out that ER might be related to an adverse outcome in patients with stable coronary artery disease., Objective: To evaluate the incidence of ER in patients with acute myocardial infarction complicated by VF., Methods: The study population consisted of 60 patients (80% men; mean age 61.8 ± 13.1 years) with acute myocardial infarction. Thirty consecutive patients (80% men; mean age 63.3 ± 12 years) admitted to our hospital had documented VF during myocardial infarction and were successfully resuscitated before hospital admission. A matched control group consisted of 30 patients (80% men; mean age 60.2 ± 14.2 years) with myocardial infarction without ventricular tachyarrhythmias. Twelve-lead electrocardiograms were analyzed for ER defined as J-point elevation ≥ 0.1 mV and "notching" and "slurring" of the terminal part of the QRS complex in at least 2 lateral or inferior leads., Results: The ER pattern was observed in 18 of the 60 patients with acute myocardial infarction. Mean elevation of the J point was 0.151 ± 0.46 mV. Notching of the J wave was observed in 14 of the 18 patients and slurring in 4 of the 18 patients. ER was more common in patients with myocardial infarction complicated by VF than in patients with myocardial infarction without ventricular tachyarrhythmias (47% vs 13%; P = .005). There have been no statistical differences in the distribution of ER in the 12-lead electrocardiogram (inferior 39% vs lateral 33% vs inferolateral 28%; P >.05)., Conclusion: Early repolarization pattern seems to be associated with ventricular tachyarrhythmias in the setting of acute myocardial infarction., (Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Published
2012
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6. 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

7. SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups

Author

Michael J. Ackerman, Sonia Franciosi, Carla Spazzolini, Peter J. Schwartz, Laura Zahavich, Annika Winbo, Anna Joong, Hervé Le Marec, Arja S. Vink, Andrew D. Krahn, Isabelle Denjoy, Mangesh Jadhav, Béatrice Guyomarc’h-Delasalle, Virginie Beauséjour-Ladouceur, Johan M Bos, Nico A. Blom, Alban-Elouen Baruteau, Matthias Lachaud, Claudine Rieubland, Jean Marc Lupoglazoff, Minoru Horie, Yanushi D. Wijeyeratne, Peter C. Ruben, Mena Abdelsayed, Jonathan R. Skinner, Elijah R. Behr, George F. Van Hare, Dominic Abrams, Takeshi Aiba, Jean-Baptiste Gourraud, Arthur A.M. Wilde, Junichi Ozawa, Tak-cheung Yung, Wataru Shimizu, Jacob Tfelt-Hansen, Leonardo Liberman, Lia Crotti, Sit Yee Kwok, Anne M. Dubin, David J. Tester, Shubhayan Sanatani, Vincent Probst, Juan Pablo Kaski, Andrew M. Davis, Federica Dagradi, Elizabeth A. Stephenson, Véronique Fressart, Boris Rudic, Leonie C.H. Wong, F. Kyndt, Jean-Jacques Schott, Baruteau, A, Kyndt, F, Behr, E, Vink, A, Lachaud, M, Joong, A, Schott, J, Horie, M, Denjoy, I, Crotti, L, Shimizu, W, Bos, J, Stephenson, E, Wong, L, Abrams, D, Davis, A, Winbo, A, Dubin, A, Sanatani, S, Liberman, L, Kaski, J, Rudic, B, Kwok, S, Rieubland, C, Tfelt-Hansen, J, Van Hare, G, Guyomarc'h-Delasalle, B, Blom, N, Wijeyeratne, Y, Gourraud, J, Le Marec, H, Ozawa, J, Fressart, V, Lupoglazoff, J, Dagradi, F, Spazzolini, C, Aiba, T, Tester, D, Zahavich, L, Beauséjour-Ladouceur, V, Jadhav, M, Skinner, J, Franciosi, S, Krahn, A, Abdelsayed, M, Ruben, P, Yung, T, Ackerman, M, Wilde, A, Schwartz, P, Probst, V, Amsterdam Cardiovascular Sciences, Graduate School, ACS - Heart failure & arrhythmias, Cardiology, and Paediatric Cardiology

Subjects
0301 basic medicine, Male, medicine.medical_specialty, BIO/18 - GENETICA, 610 Medicine & health, 030204 cardiovascular system & hematology, Lower risk, Asymptomatic, NAV1.5 Voltage-Gated Sodium Channel, 03 medical and health sciences, Electrocardiography, 0302 clinical medicine, Cardiac Conduction System Disease, Interquartile range, Loss of Function Mutation, Risk Factors, Internal medicine, Genotype, Cardiac conduction, Medicine, Humans, Child, Genetic Association Studies, Brugada syndrome, Brugada Syndrome, Retrospective Studies, business.industry, Age Factors, Infant, Newborn, Infant, Retrospective cohort study, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, medicine.disease, Brugada syndrome, Genotype–phenotype correlation, Long QT syndrome, Progressive cardiac conduction disorders, SCN5A, Sodium channelopathy, Long QT Syndrome, 030104 developmental biology, Child, Preschool, Gain of Function Mutation, Cohort, Asymptomatic Diseases, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Follow-Up Studies
Abstract

Aims To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification. Methods and results A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤ 16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutation localized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation, age ≤ 1 year at diagnosis in probands and age ≤ 1 year at diagnosis in non-probands were independent predictors of CE. Conclusion In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the most prevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent risk factors were identified, including age ≤ 1 year at diagnosis, compound mutation, and mutation with both gain- and loss-of-function.

Published
2017

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