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1. Variant interpretation in molecular autopsy: a useful dilemma

Author

Stefanie Scheiper-Welling, Monika Tabunscik, Theresa E. Gross, Tina Jenewein, Britt M. Beckmann, Constanze Niess, Elise Gradhand, Cora Wunder, Peter M. Schneider, Markus A. Rothschild, Marcel A. Verhoff, and Silke Kauferstein

Subjects
Pathology and Forensic Medicine
Abstract

Sudden cardiac death (SCD) in adolescents and young adults may be the first manifestation of an inherited arrhythmic syndrome. Thus identification of a genetic origin in sudden death cases deemed inconclusive after a comprehensive autopsy and may help to reduce the risk of lethal episodes in the remaining family. Using next-generation sequencing (NGS), a large number of variants of unknown significance (VUS) are detected. In the majority of cases, there is insufficient evidence of pathogenicity, representing a huge dilemma in current genetic investigations. Misinterpretation of such variants may lead to inaccurate genetic diagnoses and/or the adoption of unnecessary and/or inappropriate therapeutic approaches. In our study, we applied current (ACMG) recommendations for variant classification in post-mortem genetic screening of a cohort of 56 SCD victims. We identified a total 53 rare protein-altering variants (MAF

Published
2022

2. Defective Desmosomal Adhesion Causes Arrhythmogenic Cardiomyopathy by Involving an Integrin-αVβ6/TGF-β Signaling Cascade

Author

Camilla Schinner, Lifen Xu, Henriette Franz, Aude Zimmermann, Marie-Therès Wanuske, Maitreyi Rathod, Pauline Hanns, Florian Geier, Pawel Pelczar, Yan Liang, Vera Lorenz, Chiara Stüdle, Piotr I. Maly, Silke Kauferstein, Britt M. Beckmann, Farah Sheikh, Gabriela M. Kuster, and Volker Spindler

Subjects
Mice, Integrins, Transforming Growth Factor beta, Physiology (medical), Transforming Growth Factors, Animals, Arrhythmias, Cardiac, Myocytes, Cardiac, Cardiology and Cardiovascular Medicine, Cardiomyopathies, Fibrosis, Arrhythmogenic Right Ventricular Dysplasia
Abstract

Background: Arrhythmogenic cardiomyopathy (ACM) is characterized by progressive loss of cardiomyocytes with fibrofatty tissue replacement, systolic dysfunction, and life-threatening arrhythmias. A substantial proportion of ACM is caused by mutations in genes of the desmosomal cell–cell adhesion complex, but the underlying mechanisms are not well understood. In the current study, we investigated the relevance of defective desmosomal adhesion for ACM development and progression. Methods: We mutated the binding site of DSG2 (desmoglein-2), a crucial desmosomal adhesion molecule in cardiomyocytes. This DSG2-W2A mutation abrogates the tryptophan swap, a central interaction mechanism of DSG2 on the basis of structural data. Impaired adhesive function of DSG2-W2A was confirmed by cell–cell dissociation assays and force spectroscopy measurements by atomic force microscopy. The DSG2-W2A knock-in mouse model was analyzed by echocardiography, ECG, and histologic and biomolecular techniques including RNA sequencing and transmission electron and superresolution microscopy. The results were compared with ACM patient samples, and their relevance was confirmed in vivo and in cardiac slice cultures by inhibitor studies applying the small molecule EMD527040 or an inhibitory integrin-αVβ6 antibody. Results: The DSG2-W2A mutation impaired binding on molecular level and compromised intercellular adhesive function. Mice bearing this mutation develop a severe cardiac phenotype recalling the characteristics of ACM, including cardiac fibrosis, impaired systolic function, and arrhythmia. A comparison of the transcriptome of mutant mice with ACM patient data suggested deregulated integrin-αVβ6 and subsequent transforming growth factor–β signaling as driver of cardiac fibrosis. Blocking integrin-αVβ6 led to reduced expression of profibrotic markers and reduced fibrosis formation in mutant animals in vivo. Conclusions: We show that disruption of desmosomal adhesion is sufficient to induce a phenotype that fulfils the clinical criteria to establish the diagnosis of ACM, confirming the dysfunctional adhesion hypothesis. Deregulation of integrin-αVβ6 and transforming growth factor–β signaling was identified as a central step toward fibrosis. A pilot in vivo drug test revealed this pathway as a promising target to ameliorate fibrosis. This highlights the value of this model to discern mechanisms of cardiac fibrosis and to identify and test novel treatment options for ACM.

Published
2022

3. Variant interpretation in molecular autopsy: a useful dilemma

Author

Stefanie, Scheiper-Welling, Monika, Tabunscik, Theresa E, Gross, Tina, Jenewein, Britt M, Beckmann, Constanze, Niess, Elise, Gradhand, Cora, Wunder, Peter M, Schneider, Markus A, Rothschild, Marcel A, Verhoff, and Silke, Kauferstein

Subjects
Cohort Studies, Young Adult, Death, Sudden, Cardiac, Adolescent, High-Throughput Nucleotide Sequencing, Humans, Autopsy, Genetic Testing
Abstract

Sudden cardiac death (SCD) in adolescents and young adults may be the first manifestation of an inherited arrhythmic syndrome. Thus identification of a genetic origin in sudden death cases deemed inconclusive after a comprehensive autopsy and may help to reduce the risk of lethal episodes in the remaining family. Using next-generation sequencing (NGS), a large number of variants of unknown significance (VUS) are detected. In the majority of cases, there is insufficient evidence of pathogenicity, representing a huge dilemma in current genetic investigations. Misinterpretation of such variants may lead to inaccurate genetic diagnoses and/or the adoption of unnecessary and/or inappropriate therapeutic approaches. In our study, we applied current (ACMG) recommendations for variant classification in post-mortem genetic screening of a cohort of 56 SCD victims. We identified a total 53 rare protein-altering variants (MAF 0.2%) classified as VUS or worse. Twelve percent of the cases exhibited a clinically actionable variant (pathogenic, likely pathogenic or VUS - potentially pathogenic) that would warrant cascade genetic screening in relatives. Most of the variants detected by means of the post-mortem genetic investigations were VUS. Thus, genetic testing by itself might be fairly meaningless without supporting background data. This data reinforces the need for an experienced multidisciplinary team for obtaining reliable and accountable interpretations of variant significance for elucidating potential causes for SCDs in the young. This enables the early identification of relatives at risk or excludes family members as genetic carriers. Also, development of adequate forensic guidelines to enable appropriate interpretation of rare genetic variants is fundamental.

Published
2021

4. Clinical utility gene card for: Long-QT syndrome

Author

Eric Schulze-Bahr, Stefan Kääb, Arthur A.M. Wilde, Stefanie Scheiper-Welling, Britt M. Beckmann, Silke Kauferstein, Cardiology, and ACS - Heart failure & arrhythmias

Subjects
business.industry, Long QT syndrome, MEDLINE, medicine.disease, Bioinformatics, Sensitivity and Specificity, Ion Channels, Genetic Heterogeneity, Long QT Syndrome, Phenotype, Cardiovascular diseases, Genetics research, Mutation, Genetics, Humans, Medicine, Genetic Testing, business, Gene, Genetics (clinical), Clinical Utility Gene Card Update
Published
2021

5. 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

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. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Author

Yuki Bradford, Toshiko Tanaka, Jeffrey R. O'Connell, Florence Kyndt, Unnur Thorsteinsdottir, Ivana Kolcic, Xiaoyan Yin, Vincent Probst, Manolis Kellis, Christopher Newton-Cheh, Stefan Kääb, Argelia Medeiros-Domingo, Markus M. Nöthen, Paolo Gasparini, Jean-Jacques Schott, Ruth J. F. Loos, Thomas W. Mühleisen, Annukka Marjamaa, Morris Brown, Igor Rudan, Runjun D. Kumar, Peter J. Schwartz, Lars Lind, Martina Müller-Nurasyid, Xinchen Wang, Joshua C. Denny, Roberto Insolia, Soumya Raychaudhuri, Stephen W. Scherer, Bruno H. Stricker, Alexander Kluttig, Adamo Pio D'Adamo, Laurie A. Boyer, Moritz F. Sinner, Norbert Frey, Nour Eddine El Mokhtari, Thomas Meitinger, Jesper V. Olsen, Gerjan Navis, Steven R. Cummings, Richard W Morris, Nynke Hofman, Marcel den Hoed, Rudolf A. de Boer, Gonçalo R. Abecasis, Mark J. Daly, Dan M. Roden, Christian Gieger, Lyudmyla Kedenko, Marcus Dörr, Thomas P. Cappola, Afshin Parsa, Kari Stefansson, Markus Perola, Mark Eijgelsheim, Fredrik Nyberg, Robert M. Hamilton, Yalda Jamshidi, W. H. Linda Kao, Terho Lehtimäki, Annette Peters, David Schlessinger, Peter P. Pramstaller, James F. Wilson, Vilmundur Gudnason, Florian Kronenberg, Aroon D. Hingorani, Connie R. Bezzina, Abdennasser Bardai, Marylyn D. Ritchie, Andrew S. Plump, Johan Sundström, Daryl Waggott, Chrysoula Dalageorgou, Paul I.W. de Bakker, Uwe Völker, Aaron Isaacs, Oscar H. Franco, Yongmei Liu, Andrew N. Nicolaides, Lia Crotti, Cornelia M. van Duijn, Ben A. Oostra, Arne Pfeufer, Karl Werdan, Michael Morley, Jan A. Kors, Julien Barc, Lewin Eisele, Siegfried Perz, Stéphanie Chatel, Pieter A. van der Vleuten, Sara L. Pulit, Anna F. Dominiczak, Harry Campbell, Alice Ghidoni, Irene Mateo Leach, Nona Sotoodehnia, Nina Mononen, Henriette E. Meyer zu Schwabedissen, Alvaro Alonso, Fabiola Del Greco M, Dan E. Arking, Vera Adamkova, Mike A. Nalls, Valur Emilsson, Edward G. Lakatta, Kirill Tarasov, Alan F. Wright, Lenore J. Launer, Erik Ingelsson, Karin Halina Greiser, Ozren Polasek, Massimo Carella, Daniel F. Gudbjartsson, Bouwe P. Krijthe, Hanna Prucha, Per Hoffmann, Maura Griffin, Stefan Kiechl, Angel Carracedo, Ilja M. Nolte, Christine E. Moravec, Johann Willeit, Joshua C. Bis, Patricia B. Munroe, Marcello Ricardo Paulista Markus, Hailiang Huang, Mika Kähönen, Albert Hofman, Peter H. Whincup, Dirk J. van Veldhuisen, Michael Knoflach, Alicia Lundby, Serena Sanna, Hagen Kälsch, Bernhard Paulweber, Kamil Slowikowski, Luigi Ferrucci, Melanie Waldenberger, Marco Bobbo, Annukka M. Lahtinen, Ann-Christine Syvänen, J. Gustav Smith, Åsa Torinsson Naluai, Jaroslav A. Hubacek, Jeffrey Brandimarto, Wendy S. Post, Lude Franke, Mark J. Caulfield, Folkert W. Asselbergs, André G. Uitterlinden, Stefan Gustafsson, Pim van der Harst, David J. Tester, David S. Siscovick, David O. Arnar, Sarah H Wild, Elizabeth J. Rossin, Albert V. Smith, Bruce M. Psaty, Georg Ehret, Alan R. Shuldiner, Stephen Newhouse, Kimmo Kontula, Maria Brion, Andre Franke, Peter W. Macfarlane, Mika Kivimäki, Tamara B. Harris, Lasse Oikarinen, Tamara T. Koopmann, Kenneth B. Margulies, Aravinda Chakravarti, Gianfranco Sinagra, Maarten P. van den Berg, Veikko Salomaa, Karl-Heinz Jöckel, Daniel S. Evans, Caroline Hayward, Kimmo Porthan, Michael J. Ackerman, Jacqueline C.M. Witteman, Arthur A.M. Wilde, Martin G. Larson, Kasper Lage, Manuela Uda, Susan R. Heckbert, Joel S. Bader, Graham Watt, María Dolores Torres, Stephan B. Felix, Jerome I. Rotter, Pau Navarro, Meena Kumari, Johan Ärnlöv, Andrew D. Paterson, Antti Jula, Olli T. Raitakari, Raimund Erbel, Christopher J. O'Donnell, Britt M. Beckmann, Peter A. Noseworthy, Tim D. Spector, Wai K. Lee, Leopoldo Zelante, Nilesh J. Samani, John R. Giudicessi, Harold Snieder, Dag S. Thelle, David Ellinghaus, Eimo Martens, James B. Strait, Jorma S. A. Viikari, Andrew D. Johnson, Antonella Mulas, Hilma Holm, Johannes Haerting, Annamaria Iorio, Rebecca L. Zuvich, Sheila Ulivi, Andrew A. Hicks, Elijah R. Behr, Leo-Pekka Lyytikäinen, Bernhard Strohmer, Marco Orru, Claudia Lamina, Sandosh Padmanabhan, Christian Fuchsberger, Andrie G. Panayiotou, Ehret, Georg Benedikt, Internal Medicine, Public Health, Epidemiology, Rehabilitation Medicine, Medical Informatics, Clinical Genetics, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Ethical, Legal, Social Issues in Genetics (ELSI), Stem Cell Aging Leukemia and Lymphoma (SALL), Arking, D, Pulit, S, Crotti, L, van der Harst, P, Munroe, P, Koopmann, T, Sotoodehnia, N, Rossin, E, Morley, M, Wang, X, Johnson, A, Lundby, A, Gudbjartsson, D, Noseworthy, P, Eijgelsheim, M, Bradford, Y, Tarasov, K, Dörr, M, Müller-Nurasyid, M, Lahtinen, A, Nolte, I, Smith, A, Bis, J, Isaacs, A, Newhouse, S, Evans, D, Post, W, Waggott, D, Lyytikäinen, L, Hicks, A, Eisele, L, Ellinghaus, D, Hayward, C, Navarro, P, Ulivi, S, Tanaka, T, Tester, D, Chatel, S, Gustafsson, S, Kumari, M, Morris, R, Naluai, A, Padmanabhan, S, Kluttig, A, Strohmer, B, Panayiotou, A, Torres, M, Knoflach, M, Hubacek, J, Slowikowski, K, Raychaudhuri, S, Kumar, R, Harris, T, Launer, L, Shuldiner, A, Alonso, A, Bader, J, Ehret, G, Huang, H, Kao, W, Strait, J, Macfarlane, P, Brown, M, Caulfield, M, Samani, N, Kronenberg, F, Willeit, J, Smith, J, Greiser, K, Meyer Zu Schwabedissen, H, Werdan, K, Carella, M, Zelante, L, Heckbert, S, Psaty, B, Rotter, J, Kolcic, I, Polašek, O, Wright, A, Griffin, M, Daly, M, Arnar, D, Hólm, H, Thorsteinsdottir, U, Denny, J, Roden, D, Zuvich, R, Emilsson, V, Plump, A, Larson, M, O'Donnell, C, Yin, X, Bobbo, M, D'Adamo, A, Iorio, A, Sinagra, G, Carracedo, A, Cummings, S, Nalls, M, Jula, A, Kontula, K, Marjamaa, A, Oikarinen, L, Perola, M, Porthan, K, Erbel, R, Hoffmann, P, Jöckel, K, Kälsch, H, Nöthen, M, den Hoed, M, Loos, R, Thelle, D, Gieger, C, Meitinger, T, Perz, S, Peters, A, Prucha, H, Sinner, M, Waldenberger, M, de Boer, R, Franke, L, van der Vleuten, P, Beckmann, B, Martens, E, Bardai, A, Hofman, N, Wilde, A, Behr, E, Dalageorgou, C, Giudicessi, J, Medeiros-Domingo, A, Kyndt, F, Probst, V, Ghidoni, A, Insolia, R, Hamilton, R, Scherer, S, Brandimarto, J, Margulies, K, Moravec, C, Greco, M, Fuchsberger, C, O'Connell, J, Lee, W, Watt, G, Campbell, H, Wild, S, El Mokhtari, N, Frey, N, Asselbergs, F, Mateo Leach, I, Navis, G, van den Berg, M, van Veldhuisen, D, Kellis, M, Krijthe, B, Franco, O, Hofman, A, Kors, J, Uitterlinden, A, Witteman, J, Kedenko, L, Lamina, C, Oostra, B, Abecasis, G, Lakatta, E, Mulas, A, Orrú, M, Schlessinger, D, Uda, M, Markus, M, Völker, U, Snieder, H, Spector, T, Arnlöv, J, Lind, L, Sundström, J, Syvänen, A, Kivimaki, M, Kähönen, M, Mononen, N, Raitakari, O, Viikari, J, Adamkova, V, Kiechl, S, Brion, M, Nicolaides, A, Paulweber, B, Haerting, J, Dominiczak, A, Nyberg, F, Whincup, P, Hingorani, A, Schott, J, Bezzina, C, Ingelsson, E, Ferrucci, L, Gasparini, P, Wilson, J, Rudan, I, Franke, A, Mühleisen, T, Pramstaller, P, Lehtimäki, T, Paterson, A, Parsa, A, Liu, Y, van Duijn, C, Siscovick, D, Gudnason, V, Jamshidi, Y, Salomaa, V, Felix, S, Sanna, S, Ritchie, M, Stricker, B, Stefansson, K, Boyer, L, Cappola, T, Olsen, J, Lage, K, Schwartz, P, Kääb, S, Chakravarti, A, Ackerman, M, Pfeufer, A, de Bakker, P, Newton-Cheh, C, Arking, Dan E., Pulit, Sara L., Crotti, Lia, Van Der Harst, Pim, Munroe, Patricia B., Koopmann, Tamara T., Sotoodehnia, Nona, Rossin, Elizabeth J., Morley, Michael, Wang, Xinchen, Johnson, Andrew D., Lundby, Alicia, Gudbjartsson, Daníel F., Noseworthy, Peter A., Eijgelsheim, Mark, Bradford, Yuki, Tarasov, Kirill V., Dörr, Marcu, Müller Nurasyid, Martina, Lahtinen, Annukka M., Nolte, Ilja M., Smith, Albert Vernon, Bis, Joshua C., Isaacs, Aaron, Newhouse, Stephen J., Evans, Daniel S., Post, Wendy S., Waggott, Daryl, Lyytikäinen, Leo Pekka, Hicks, Andrew A., Eisele, Lewin, Ellinghaus, David, Hayward, Caroline, Navarro, Pau, Ulivi, Sheila, Tanaka, Toshiko, Tester, David J., Chatel, Stéphanie, Gustafsson, Stefan, Kumari, Meena, Morris, Richard W., Naluai, Asa T., Padmanabhan, Sandosh, Kluttig, Alexander, Strohmer, Bernhard, Panayiotou, Andrie G., Torres, Maria, Knoflach, Michael, Hubacek, Jaroslav A., Slowikowski, Kamil, Raychaudhuri, Soumya, Kumar, Runjun D., Harris, Tamara B., Launer, Lenore J., Shuldiner, Alan R., Alonso, Alvaro, Bader, Joel S., Ehret, Georg, Huang, Hailiang, Kao, W. H. Linda, Strait, James B., Macfarlane, Peter W., Brown, Morri, Caulfield, Mark J., Samani, Nilesh J., Kronenberg, Florian, Willeit, Johann, Smith, J. Gustav, Greiser, Karin H., Zu Schwabedissen, Henriette Meyer, Werdan, Karl, Carella, Massimo, Zelante, Leopoldo, Heckbert, Susan R., Psaty, Bruce M., Rotter, Jerome I., Kolcic, Ivana, Polašek, Ozren, Wright, Alan F., Griffin, Maura, Daly, Mark J., Arnar, David O., Hólm, Hilma, Thorsteinsdottir, Unnur, Denny, Joshua C., Roden, Dan M., Zuvich, Rebecca L., Emilsson, Valur, Plump, Andrew S., Larson, Martin G., O'Donnell, Christopher J., Yin, Xiaoyan, Bobbo, Marco, D'Adamo, ADAMO PIO, Iorio, Annamaria, Sinagra, Gianfranco, Carracedo, Angel, Cummings, Steven R., Nalls, Michael A., Jula, Antti, Kontula, Kimmo K., Marjamaa, Annukka, Oikarinen, Lasse, Perola, Marku, Porthan, Kimmo, Erbel, Raimund, Hoffmann, Per, Jöckel, Karl Heinz, Kälsch, Hagen, Nöthen, Markus M., Den Hoed, Marcel, Loos, Ruth J. F., Thelle, Dag S., Gieger, Christian, Meitinger, Thoma, Perz, Siegfried, Peters, Annette, Prucha, Hanna, Sinner, Moritz F., Waldenberger, Melanie, De Boer, Rudolf A., Franke, Lude, Van Der Vleuten, Pieter A., Beckmann, Britt Maria, Martens, Eimo, Bardai, Abdennasser, Hofman, Nynke, Wilde, Arthur A. M., Behr, Elijah R., Dalageorgou, Chrysoula, Giudicessi, John R., Medeiros Domingo, Argelia, Barc, Julien, Kyndt, Florence, Probst, Vincent, Ghidoni, Alice, Insolia, Roberto, Hamilton, Robert M., Scherer, Stephen W., Brandimarto, Jeffrey, Margulies, Kenneth, Moravec, Christine E., Del Greco M, Fabiola, Fuchsberger, Christian, O'Connell, Jeffrey R., Lee, Wai K., Watt, Graham C. M., Campbell, Harry, Wild, Sarah H., El Mokhtari, Nour E., Frey, Norbert, Asselbergs, Folkert W., Leach, Irene Mateo, Navis, Gerjan, Van Den Berg, Maarten P., Van Veldhuisen, Dirk J., Kellis, Manoli, Krijthe, Bouwe P., Franco, Oscar H., Hofman, Albert, Kors, Jan A., Uitterlinden, André G., Witteman, Jacqueline C. M., Kedenko, Lyudmyla, Lamina, Claudia, Oostra, Ben A., Abecasis, Gonçalo R., Lakatta, Edward G., Mulas, Antonella, Orrú, Marco, Schlessinger, David, Uda, Manuela, Markus, Marcello R. P., Völker, Uwe, Snieder, Harold, Spector, Timothy D., Ärnlöv, Johan, Lind, Lar, Sundström, Johan, Syvänen, Ann Christine, Kivimaki, Mika, Kähönen, Mika, Mononen, Nina, Raitakari, Olli T., Viikari, Jorma S., Adamkova, Vera, Kiechl, Stefan, Brion, Maria, Nicolaides, Andrew N., Paulweber, Bernhard, Haerting, Johanne, Dominiczak, Anna F., Nyberg, Fredrik, Whincup, Peter H., Hingorani, Aroon D., Schott, Jean Jacque, Bezzina, Connie R., Ingelsson, Erik, Ferrucci, Luigi, Gasparini, Paolo, Wilson, James F., Rudan, Igor, Franke, Andre, Mühleisen, Thomas W., Pramstaller, Peter P., Lehtimäki, Terho J., Paterson, Andrew D., Parsa, Afshin, Liu, Yongmei, Van Duijn, Cornelia M., Siscovick, David S., Gudnason, Vilmundur, Jamshidi, Yalda, Salomaa, Veikko, Felix, Stephan B., Sanna, Serena, Ritchie, Marylyn D., Stricker, Bruno H., Stefansson, Kari, Boyer, Laurie A., Cappola, Thomas P., Olsen, Jesper V., Lage, Kasper, Schwartz, Peter J., Kääb, Stefan, Chakravarti, Aravinda, Ackerman, Michael J., Pfeufer, Arne, De Bakker, Paul I. W., Newton Cheh, Christopher, Cardiology, ACS - Amsterdam Cardiovascular Sciences, and Human Genetics

Subjects
Male, Candidate gene, Myocardium/metabolism, LOCI, Medizin, Heart electrophysiology, Genome-wide association study, Arrhythmias, Bioinformatics, Medical and Health Sciences, Heart Ventricle, Sudden cardiac death, Electrocardiography, PR INTERVAL, Arrhythmias, Cardiac/genetics, Death, Sudden, Cardiac/etiology, Genetics, ddc:616, Cardiac electrophysiology, Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Middle Aged, Myocardium, Polymorphism, Single Nucleotide, COMMON VARIANTS, Heart Ventricles/metabolism, Single Nucleotide, Long QT Syndrome/genetics, CHRONIC HEART-FAILURE, Death, Heart ventricle arrhythmia, genetic association study, gene, SNP, heart, Genome-Wide Association Study/methods, Long QT syndrome, QRS DURATION, Cardiac, Cardiac/etiology, Human, QT interval, congenital, hereditary, and neonatal diseases and abnormalities, Electrocardiography/methods, TRPM7, BIO/18 - GENETICA, Cardiac/genetics, Biology, Article, sudden cardiac death, QRS complex, CARDIAC REPOLARIZATION, medicine, Repolarization, cardiovascular diseases, GENOME-WIDE ASSOCIATION, Polymorphism, MED/01 - STATISTICA MEDICA, calcium, ta1184, Calcium signaling, Calcium Signaling/genetics, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, ta3121, Cardiovascular risk, medicine.disease, SARCOPLASMIC-RETICULUM, Sudden, MODEL, Genetic association, myocardial repolarization, Genetic variability, Gene expression, Clinical Medicine, genetic, Controlled study
Abstract

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain similar to 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

Published
2014

8. Incidence of sudden cardiac death in Germany: results from an emergency medical service registry in Lower Saxony

Author

Eimo Martens, Britt M. Beckmann, Stefan Veith, Stefan Kääb, Gerhard Steinbeck, Johannes Siebermair, Dieter Düvel, Moritz F. Sinner, and Carsten Raufhake

Subjects
Adult, Male, Emergency Medical Services, Pediatrics, medicine.medical_specialty, Adolescent, Epidemiology, CLINICAL RESEARCH, Resuscitation, medicine.medical_treatment, Sudden cardiac death, Young Adult, Emergency medical service, Age Distribution, Risk Factors, Germany, Physiology (medical), medicine, Emergency medical services, Humans, Registries, Sudden death and ICDs, Cardiopulmonary resuscitation, Sex Distribution, Child, Aged, Cause of death, Aged, 80 and over, business.industry, Incidence, Incidence (epidemiology), Medical record, Mortality rate, Infant, Newborn, Infant, Middle Aged, Cardiac arrest, medicine.disease, Cardiopulmonary Resuscitation, Death, Sudden, Cardiac, Child, Preschool, Female, Cardiology and Cardiovascular Medicine, business
Abstract

Aims Sudden cardiac death (SCD) is among the most common causes of death in western countries including Germany. Whereas risk stratification and primary prevention is still insufficient, we also lack accurate incidence estimates. Current estimates vary widely (18.6–128/100 000/year), but data on SCD incidence in Germany are missing. Depending on SCD definitions, death needs to occur between 1 and 24 h after the onset of symptoms. Methods and results In the district of Aurich (190 000 inhabitants, Lower Saxony, Germany), emergency medical service (EMS) is provided by a district government operated single carrier and two hospitals. To evaluate all EMS calls in this district from 2002 to 2009, we obtained EMS protocols, medical records, and death certificates for data analysis and adjudication of SCD. We defined SCD according to the definition of the World Health Organization, considering patients with cardiac arrest within ≤1 h after the onset of symptoms. We also required cardiopulmonary resuscitation being performed by EMS personnel. The overall mortality rate in the district of Aurich (1060/100 000/year) corresponded well with the average mortality rate in Germany (1030/100 000/year). During the observation period, we adjudicated 1212 SCD cases, equivalent to an annual rate of 151 SCD cases (81 cases/100 000/year). Rates remained remarkably stable over time, and affected a considerable number of individuals of working age (32/100 000/year). Conclusion Consistent with prior reports, the SCD incidence in a district of Germany is substantial. Despite an elaborate EMS system and advanced medical care, SCD rates remain stable and necessitate improved, individualized risk stratification.

Published
2014

9. Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death

Author

Jade Violleau, Stefan Kääb, Susan Bartkowiak, Richard Redon, Antoine Leenhardt, Hanno L. Tan, Jean-Baptiste Gourraud, Peter Weeke, Rachel Bastiaenen, Rianne Wolswinkel, Federica Dagradi, Vincent M. Christoffels, Jacob Tfelt-Hansen, Jean-Jacques Schott, Hervé Le Marec, Manfred Gessler, Françoise Gros, Pascale Guicheney, Julien Barc, Arthur A.M. Wilde, Simon Lecointe, Akihiko Nogami, Tohru Minamino, Sven Zumhagen, Margherita Torchio, Elijah R. Behr, Rainer Schimpf, Carol Ann Remme, Florence Kyndt, Lia Crotti, Yuka Mizusawa, Morten S. Olesen, Vincent Probst, Naoto Endo, Naomasa Makita, Eric Charpentier, Philippe Froguel, Arie O. Verkerk, Minoru Horie, Takeshi Aiba, Christian Dina, Peter J. Schwartz, Kanae Hasegawa, Floriane Simonet, Véronique Fressart, Seiko Ohno, Cornelia Wiese, Eric Schulze-Bahr, Stéphane Bézieau, Hiroshi Watanabe, Vincent Portero, Wataru Shimizu, Beverley Balkau, Martin Borggrefe, Britt M. Beckmann, Charles Antzelevitch, Bas J. Boukens, Dan M. Roden, Pierre Lindenbaum, Aurore Despres, David Weber, Olivier Lantieri, Connie R. Bezzina, Stéphanie Chatel, Ruben Coronel, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Medical Biology, Other departments, ARD - Amsterdam Reproduction and Development, Bezzina, C, Barc, J, Mizusawa, Y, Remme, C, Gourraud, J, Simonet, F, Verkerk, A, Schwartz, P, Crotti, L, Dagradi, F, Guicheney, P, Fressart, V, Leenhardt, A, Antzelevitch, C, Bartkowiak, S, Borggrefe, M, Schimpf, R, Schulze-Bahr, E, Zumhagen, S, Behr, E, Bastiaenen, R, Tfelt-Hansen, J, Olesen, M, Kääb, S, Beckmann, B, Weeke, P, Watanabe, H, Endo, N, Minamino, T, Horie, M, Ohno, S, Hasegawa, K, Makita, N, Nogami, A, Shimizu, W, Aiba, T, Froguel, P, Balkau, B, Lantieri, O, Torchio, M, Wiese, C, Weber, D, Wolswinkel, R, Coronel, R, Boukens, B, Bézieau, S, Charpentier, E, Chatel, S, Despres, A, Gros, F, Kyndt, F, Lecointe, S, Lindenbaum, P, Portero, V, Violleau, J, Gessler, M, Tan, H, Roden, D, Christoffels, V, Le Marec, H, Wilde, A, Probst, V, Schott, J, Dina, C, and Redon, R

Subjects
Male, Qrs Duration, Bioinformatics, Sodium Channels, NAV1.5 Voltage-Gated Sodium Channel, Sudden cardiac death, Genome-Wide Association, Mice, Atrial Gene-Expression, Basic Helix-Loop-Helix Transcription Factors, Odds Ratio, Brugada Syndrome, Brugada syndrome, Mice, Knockout, St-Segment Elevation, SECS-S/01 - STATISTICA, cardiovascular system, Cardiology, Chromosomes, Human, Pair 6, Female, Chromosomes, Human, Pair 3, medicine.medical_specialty, Bundle-Branch Block, BIO/18 - GENETICA, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, NAV1.8 Voltage-Gated Sodium Channel, Internal medicine, Genetic variation, Cardiac conduction, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, cardiovascular diseases, HEY2, Alleles, Heart-Rate, Genetic Variation, Cardiac arrhythmia, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, medicine.disease, Qt Interval Duration, Repressor Proteins, Ventricular-Fibrillation, Pr Interval, Death, Sudden, Cardiac, Case-Control Studies, Conduction System, Genome-Wide Association Study, Rare disease
Abstract

Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10(-68); rs9388451, P = 5.1 × 10(-17)) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10(-14)). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10(-81)). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.

Published
2013

10. Not All Beta-Blockers Are Equal in the Management of Long QT Syndrome Types 1 and 2

Author

Stefan Kääb, Priya Chockalingam, Lia Crotti, Arthur A.M. Wilde, Freek van den Heuvel, Jeroen F. van der Heijden, Jonathan N. Johnson, Peter J. Schwartz, Giulia Girardengo, Nico A. Blom, Richard N.W. Hauer, Roberto Rordorf, Markus Fischer, Katy M. Harris, Michael J. Ackerman, S. A. Clur, Britt M. Beckmann, Carla Spazzolini, Annika Rydberg, Paediatric Cardiology, ACS - Amsterdam Cardiovascular Sciences, AII - Amsterdam institute for Infection and Immunity, APH - Amsterdam Public Health, Cardiology, and Faculteit Medische Wetenschappen/UMCG

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Long QT syndrome, Propranolol, PHENOTYPE, QT interval, THERAPY, Adrenergic beta-Antagonists, breakthrough cardiac events, EVENTS, FAILURES, Nadolol, Internal medicine, Medicine, nadolol, cardiovascular diseases, propranolol, Survival analysis, Metoprolol, RISK, medicine.diagnostic_test, business.industry, congenital long QT syndrome, medicine.disease, EFFICACY, metoprolol, GENOTYPE, Endocrinology, Cardiology, business, Cardiology and Cardiovascular Medicine, Electrocardiography, circulatory and respiratory physiology, medicine.drug
Abstract

Objectives The purpose of this study was to compare the efficacy of beta-blockers in congenital long QT syndrome (LQTS). Background Beta-blockers are the mainstay in managing LQTS. Studies comparing the efficacy of commonly used beta-blockers are lacking, and clinicians generally assume they are equally effective. Methods Electrocardiographic and clinical parameters of 382 LQT1/LQT2 patients initiated on propranolol (n = 134), metoprolol (n = 147), and nadolol (n = 101) were analyzed, excluding patients 480 ms. None of the asymptomatic patients had BCEs. Among symptomatic patients (n = 101), 15 had BCEs (all syncopes). The QTc shortening was significantly less pronounced among patients with BCEs. There was a greater risk of BCEs for symptomatic patients initiated on metoprolol compared to users of the other 2 beta-blockers combined, after adjustment for genotype (odds ratio: 3.95, 95% confidence interval: 1.2 to 13.1, p = 0.025). Kaplan-Meier analysis showed a significantly lower event-free survival for symptomatic patients receiving metoprolol compared to propranolol/nadolol. Conclusions Propranolol has a significantly better QTc shortening effect compared to metoprolol and nadolol, especially in patients with prolonged QTc. Propranolol and nadolol are equally effective, whereas symptomatic patients started on metoprolol are at a significantly higher risk for BCEs. Metoprolol should not be used for symptomatic LQT1 and LQT2 patients. (J Am Coll Cardiol 2012;60:2092-9) (C) 2012 by the American College of Cardiology Foundation

Published
2012

11. Common variants in KCNN3 are associated with lone atrial fibrillation

Author

Gerhard Steinbeck, John Barnard, Dan M. Roden, Tamara B. Harris, Calum A. MacRae, Moritz F. Sinner, David R. Van Wagoner, Lenore J. Launer, Seiko Makino, Eric J. Topol, Siegfried Perz, Thomas J. Wang, Aravinda Chakravarti, Ke Wang, Kathryn L. Lunetta, Markus M. Nöthen, Mina K. Chung, Elsayed Z. Soliman, Stefan Kääb, David J. Milan, Mari Nelis, Stanley L. Hazen, Arne Pfeufer, Thomas Meitinger, Daniel Levy, Dawood Darbar, Susanne Moebus, Andres Metspalu, Jacqueline C.M. Witteman, Vilmundur Gudnason, Jonathan D. Smith, Albert Hofman, Anna Köttgen, Susan R. Heckbert, Paul I.W. de Bakker, Emelia J. Benjamin, Kenneth Rice, Britt-M. Beckmann, Ramachandran S. Vasan, Charlotte van Noord, Eric Boerwinkle, Stefan Möhlenkamp, Martina Mueller, Bruce M. Psaty, Alvaro Alonso, Dan E. Arking, H.-Erich Wichmann, Christopher Newton-Cheh, Man Li, Nicole L. Glazer, André G. Uitterlinden, Georg Ehret, Tõnu Esko, Bruno H. Stricker, Nicholas L. Smith, W. H. Linda Kao, Albert V. Smith, Steven A. Lubitz, Jerome I. Rotter, Patrick T. Ellinor, Renate B. Schnabel, Ervin R. Fox, Epidemiology, and Internal Medicine

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Heart disease, Small-Conductance Calcium-Activated Potassium Channels, Medizin, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, Cohort Studies, Young Adult, Meta-Analysis as Topic, Polymorphism (computer science), Internal medicine, Atrial Fibrillation, Genetics, medicine, Humans, Aged, Genetic association, Case-control study, Atrial fibrillation, Odds ratio, Middle Aged, medicine.disease, Introns, Endocrinology, Case-Control Studies, Cardiology, Female, Genome-Wide Association Study, Cohort study
Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

Published
2010

12. The common non-synonymous variant G38S of the KCNE1-(minK)-gene is not associated to QT interval in Central European Caucasians: results from the KORA study

Author

Stefan Kääb, Christian Gieger, Arne Pfeufer, Siegfried Perz, Shapour Jalilzadeh, Thomas Meitinger, Britt M. Beckmann, Thomas Illig, Mahmut Akyol, Moritz F. Sinner, and H.-Erich Wichmann

Subjects
Adult, Male, Genotype, hERG, Population, Polymorphism, Single Nucleotide, Sudden death, QT interval, Genetic determinism, Electrocardiography, Gene Frequency, Heart Conduction System, Polymorphism (computer science), Humans, Medicine, education, Aged, Genetics, education.field_of_study, biology, business.industry, DNA, Middle Aged, Heritability, Genetic epidemiology, Potassium Channels, Voltage-Gated, biology.protein, Female, Cardiology and Cardiovascular Medicine, business
Abstract

Aims The QT interval in the general population is a complex trait with 30–50% heritability. QT prolongation is associated with an increased risk of sudden death. A recent family-based study found an association between QT interval and the common non-synonymous Glycin 38 Serine variant (G38S, rs1805127) of the KCNE1 gene coding for the minK-potassium channel subunit. We intended to replicate this finding in a large population sample of central European Caucasian ancestry as part of our ongoing search for genetic variants predisposing to arrhythmias. Methods and results We studied 3966 unrelated individuals from the KORA S4 population-based study without atrial fibrillation, pacemaker implant, or pregnancy. Individuals were genotyped by MALDI-TOF mass spectrometry. We did not detect any significant association between the genotypes of the G38S variant and the QT interval in the entire population or in any gender. Conclusion Unlike the common Lysine 897 Threonine variant of KCNH2 (K897T, rs1805123) the G38S variant of KCNE1 does not appear to have a strong modifying effect on QT interval. However, we cannot rule out an effect of G38S on QT in other ethnic groups, under exercise or medications or on the risk for arrhythmias and sudden death.

Published
2007

13. Torsades de Pointes: A Rare Complication of an Extra-Adrenal Pheochromocytoma

Author

Gerhard Steinbeck, Ute Wilbert-Lampen, Stefan Kääb, Martin Hinterseer, Britt M. Beckmann, and Heiko Methe

Subjects
Adult, endocrine system, medicine.medical_specialty, Hypertensive encephalopathy, endocrine system diseases, Physiology, Long QT syndrome, Adrenal Gland Neoplasms, Cardiomyopathy, Torsades de pointes, Pheochromocytoma, Sudden death, Electrocardiography, Risk Factors, Torsades de Pointes, Internal medicine, Internal Medicine, medicine, Palpitations, Humans, business.industry, Sotalol, medicine.disease, Heart failure, Anesthesia, Cardiology, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Anti-Arrhythmia Agents
Abstract

Pheochromocytoma is an infrequent secondary cause of arterial hypertension, often associated with paroxysmal headache, sweating, weight loss, and palpitations. Cardiovascular complications of pheochromocytoma include sudden death, heart failure due to toxic cardiomyopathy, and hypertensive encephalopathy. Here we report the case of a female with an acquired long-QT-syndrome as a rare complication of an extra-adrenal pheochromocytoma. Diagnosis was made after sotalol-induced Torsades de Pointes.

Published
2007

14. Analysis for Genetic Modifiers of Disease Severity in Patients With Long-QT Syndrome Type 2

Author

Stefan Kääb, Sven Zumhagen, Julien Barc, Thomas Meitinger, Jean-Jacques Schott, Nynke Hofman, Pieter G. Postema, Arthur A.M. Wilde, Peter Lichtner, Nanette H. Bishopric, Connie R. Bezzina, Robert J. Myerburg, Dan M. Roden, A. Pfeufer, Tamara T. Koopmann, Anja Husemann, Birgit Stallmeyer, Moritz F. Sinner, Eric Schulze-Bahr, Iris C. R. M. Kolder, Michael W.T. Tanck, Britt M. Beckmann, APH - Amsterdam Public Health, Epidemiology and Data Science, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Human Genetics, 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), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Genetics of Heart Diseases, University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Interdisziplinary Clinical Research Center (IZKF), Institute of Human Genetics, German Research Center for Environmental Health, and Helmholtz-Zentrum München (HZM)

Subjects
Male, Genotype, Long QT syndrome, [SDV]Life Sciences [q-bio], Adrenergic beta-Antagonists, Genome-wide association study, Biology, Arrhythmias, Bioinformatics, Severity of Illness Index, Article, Ion Channels, Electrocardiography, Polymorphism (computer science), Risk Factors, Severity of illness, Genetics, medicine, Odds Ratio, long QT syndrome, Allele, Polymorphism, humans, Genetics (clinical), Alleles, Arrhythmia, Association Study, Genetic Risk Score, Ion Channel, Long Qt Syndrome, Polymorphism Genetics, Case-control study, Signal Transducing, Adaptor Proteins, Odds ratio, Single Nucleotide, medicine.disease, Case-Control Studies, KCNQ1 Potassium Channel, Female, Cardiology and Cardiovascular Medicine, Cardiac, Genome-Wide Association Study
Abstract

Background— Considerable interest exists in the identification of genetic modifiers of disease severity in the long-QT syndrome (LQTS) as their identification may contribute to refinement of risk stratification. Methods and Results— We searched for single-nucleotide polymorphisms (SNPs) that modulate the corrected QT (QTc)-interval and the occurrence of cardiac events in 639 patients harboring different mutations in KCNH2 . We analyzed 1201 SNPs in and around 18 candidate genes, and in another approach investigated 22 independent SNPs previously identified as modulators of QTc-interval in genome-wide association studies in the general population. In an analysis for quantitative effects on the QTc-interval, 3 independent SNPs at NOS1AP (rs10494366, P =9.5×10 −8 ; rs12143842, P =4.8×10 −7 ; and rs2880058, P =8.6×10 −7 ) were strongly associated with the QTc-interval with marked effects (>12 ms/allele). Analysis of patients versus general population controls uncovered enrichment of QTc-prolonging alleles in patients for 2 SNPs, located respectively at NOS1AP (rs12029454; odds ratio, 1.85; 95% confidence interval, 1.32–2.59; P =3×10 −4 ) and KCNQ1 (rs12576239; odds ratio, 1.84; 95% confidence interval, 1.31–2.60; P =5×10 −4 ). An analysis of the cumulative effect of the 6 NOS1AP SNPs by means of a multilocus genetic risk score (GRS NOS1AP ) uncovered a strong linear relationship between GRS NOS1AP and the QTc-interval ( P =4.2×10 −7 ). Furthermore, patients with a GRS NOS1AP in the lowest quartile had a lower relative risk of cardiac events compared with patients in the other quartiles combined ( P =0.039). Conclusions— We uncovered unexpectedly large effects of NOS1AP SNPs on the QTc-interval and a trend for effects on risk of cardiac events. For the first time, we linked common genetic variation at KCNQ1 with risk of long-QT syndrome.

Published
2015

15. Novel calmodulin mutations associated with congenital arrhythmia susceptibility

Author

Wataru Satake, Christopher N. Johnson, Hirokazu Yamamoto, Yoshihiro Miyamoto, Stefan Kääb, Michelle S. Roh, Pascale Guicheney, Hideki Motomura, Naoto Endo, Tessa Homfray, Naomasa Makita, Takeshi Tsuchiya, Kenji Suda, Didier Klug, Taisuke Ishikawa, Tatsushi Toda, Wataru Shimizu, Takeshi Aiba, Tatsuhiko Tsunoda, Hidewaki Nakagawa, Thomas Meitinger, Toshihiro Tanaka, Walter J. Chazin, Kouichi Ozaki, Lia Crotti, Daniel Theisen, Peter J. Schwartz, Hiroshi Watanabe, Yukiomi Tsuji, Alfred L. George, Elisa Mastantuono, Britt M. Beckmann, Isabelle Denjoy, Peter Lichtner, Daichi Shigemizu, Nobue Yagihara, Akinori Kimura, Zahurul A. Bhuiyan, Elijah R. Behr, Makita, N, Yagihara, N, Crotti, L, Johnson, C, Beckmann, B, Roh, M, Shigemizu, D, Lichtner, P, Ishikawa, T, Aiba, T, Homfray, T, Behr, E, Klug, D, Denjoy, I, Mastantuono, E, Theisen, D, Tsunoda, T, Satake, W, Toda, T, Nakagawa, H, Tsuji, Y, Tsuchiya, T, Yamamoto, H, Miyamoto, Y, Endo, N, Kimura, A, Ozaki, K, Motomura, H, Suda, K, Tanaka, T, Schwartz, P, Meitinger, T, Kääb, S, Guicheney, P, Shimizu, W, Bhuiyan, Z, Watanabe, H, Chazin, W, and George, A

Subjects
Proband, Adult, Male, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, MED/03 - GENETICA MEDICA, Long QT syndrome, Adrenergic beta-Antagonists, Molecular Sequence Data, Mutation, Missense, Biology, medicine.disease_cause, Catecholaminergic polymorphic ventricular tachycardia, Article, Sudden cardiac death, Electrocardiography, Calmodulin, Internal medicine, Genetics, medicine, Missense mutation, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Amino Acid Sequence, Age of Onset, Child, Exome, Genetics (clinical), Mutation, High-Throughput Nucleotide Sequencing, Infant, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, Sequence Analysis, DNA, medicine.disease, Pedigree, Long QT Syndrome, Endocrinology, Child, Preschool, Cardiology, Tachycardia, Ventricular, Calcium, Female, Age of onset, Cardiology and Cardiovascular Medicine, Protein Binding
Abstract

Background—Genetic predisposition to life-threatening cardiac arrhythmias such as congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (CALM1,CALM2) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype–phenotype correlations associated with calmodulin mutations.Methods and Results—We used conventional and next-generation sequencing approaches, including exome analysis, in genotype-negative LQTS probands. We identified 5 novel de novo missense mutations inCALM2in 3 subjects with LQTS (p.N98S, p.N98I, p.D134H) and 2 subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1 to 9 years. Three of 5 probands had cardiac arrest and 1 of these subjects did not survive. The clinical severity among subjects in this series was generally less than that originally reported forCALM1andCALM2associated with recurrent cardiac arrest during infancy. Four of 5 probands responded to β-blocker therapy, whereas 1 subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within Ca2+-binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced Ca2+-binding affinity.Conclusions—CALM2mutations can be associated with LQTS and with overlapping features of LQTS and CPVT.

Published
2014

16. Laminopathy presenting as familial atrial fibrillation

Author

Stefan Kääb, Britt M. Beckmann, Martin Hinterseer, Nadine Haserück, Maggie C. Walter, Arthur A.M. Wilde, Christopher Reithmann, Elke Holinski-Feder, Amsterdam Cardiovascular Sciences, and Cardiology

Subjects
medicine.medical_specialty, Heart disease, business.industry, Laminopathy, Atrial fibrillation, medicine.disease, Sudden death, Sudden cardiac death, LMNA, Internal medicine, medicine, Cardiology, Cardiology and Cardiovascular Medicine, business, Familial atrial fibrillation
Published
2010

17. Calmodulin mutations associated with recurrent cardiac arrest in infants

Author

Peter J. Schwartz, Travis Clark, Christopher N. Johnson, Tim M. Strom, Christian M. Shaffer, Thomas Meitinger, Subodh Rathi, D. Woodrow Benson, Gaetano M. De Ferrari, John Papagiannis, Elisabeth Graf, Michael D. Feldkamp, Britt M. Beckmann, Thomas Wieland, Marc Ovadia, Alfred L. George, Jennifer D. Kunic, Lia Crotti, Peter Lichtner, Matteo Pedrazzini, Walter J. Chazin, Stefan Kääb, Bettina F. Cuneo, Crotti, L, Johnson, C, Graf, E, De Ferrari, G, Cuneo, B, Ovadia, M, Papagiannis, J, Feldkamp, M, Rathi, S, Kunic, J, Pedrazzini, M, Wieland, T, Lichtner, P, Beckmann, B, Clark, T, Shaffer, C, Benson, D, Kääb, S, Meitinger, T, Strom, T, Chazin, W, Schwartz, P, and George AL, J

Subjects
Proband, Male, Candidate gene, 030204 cardiovascular system & hematology, Bioinformatics, medicine.disease_cause, Cohort Studies, 0302 clinical medicine, Arrhythmia, Calcium Signaling, Death, Sudden, Cardiac, Exome, Recurrence, Medicine, Exome sequencing, Genetics, 0303 health sciences, Mutation, 3. Good health, Pedigree, Long QT Syndrome, Child, Preschool, Cohort, Female, Cardiology and Cardiovascular Medicine, arrhythmia, calcium signaling, death, sudden, cardiac, exome, Long QT syndrome, Molecular Sequence Data, BIO/18 - GENETICA, 03 medical and health sciences, Calmodulin, Physiology (medical), Humans, Amino Acid Sequence, Gene, Genetic Association Studies, 030304 developmental biology, business.industry, Infant, Newborn, Infant, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, medicine.disease, Heart Arrest, business, Follow-Up Studies
Abstract

Background— Life-threatening disorders of heart rhythm may arise during infancy and can result in the sudden and tragic death of a child. We performed exome sequencing on 2 unrelated infants presenting with recurrent cardiac arrest to discover a genetic cause. Methods and Results— We ascertained 2 unrelated infants (probands) with recurrent cardiac arrest and dramatically prolonged QTc interval who were both born to healthy parents. The 2 parent-child trios were investigated with the use of exome sequencing to search for de novo genetic variants. We then performed follow-up candidate gene screening on an independent cohort of 82 subjects with congenital long-QT syndrome without an identified genetic cause. Biochemical studies were performed to determine the functional consequences of mutations discovered in 2 genes encoding calmodulin. We discovered 3 heterozygous de novo mutations in either CALM1 or CALM2 , 2 of the 3 human genes encoding calmodulin, in the 2 probands and in 2 additional subjects with recurrent cardiac arrest. All mutation carriers were infants who exhibited life-threatening ventricular arrhythmias combined variably with epilepsy and delayed neurodevelopment. Mutations altered residues in or adjacent to critical calcium binding loops in the calmodulin carboxyl-terminal domain. Recombinant mutant calmodulins exhibited several-fold reductions in calcium binding affinity. Conclusions— Human calmodulin mutations disrupt calcium ion binding to the protein and are associated with a life-threatening condition in early infancy. Defects in calmodulin function will disrupt important calcium signaling events in heart, affecting membrane ion channels, a plausible molecular mechanism for potentially deadly disturbances in heart rhythm during infancy.

Published
2013

18. Not all beta-blockers are equal in the management of long QT syndrome types 1 and 2: higher recurrence of events under metoprolol

Author

Priya, Chockalingam, Lia, Crotti, Giulia, Girardengo, Jonathan N, Johnson, Katy M, Harris, Jeroen F, van der Heijden, Richard N W, Hauer, Britt M, Beckmann, Carla, Spazzolini, Roberto, Rordorf, Annika, Rydberg, Sally-Ann B, Clur, Markus, Fischer, Freek, van den Heuvel, Stefan, Kääb, Nico A, Blom, Michael J, Ackerman, Peter J, Schwartz, and Arthur A M, Wilde

Subjects
Adult, Male, Adolescent, Adrenergic beta-Antagonists, Prognosis, Propranolol, Survival Analysis, Disease-Free Survival, Electrocardiography, Long QT Syndrome, Nadolol, Young Adult, Treatment Outcome, Secondary Prevention, Humans, Female, Child, Metoprolol
Abstract

The purpose of this study was to compare the efficacy of beta-blockers in congenital long QT syndrome (LQTS).Beta-blockers are the mainstay in managing LQTS. Studies comparing the efficacy of commonly used beta-blockers are lacking, and clinicians generally assume they are equally effective.Electrocardiographic and clinical parameters of 382 LQT1/LQT2 patients initiated on propranolol (n = 134), metoprolol (n = 147), and nadolol (n = 101) were analyzed, excluding patients1 year of age at beta-blocker initiation. Symptoms before therapy and the first breakthrough cardiac events (BCEs) were documented.Patients (56% female, 27% symptomatic, heart rate 76 ± 16 beats/min, QTc 472 ± 46 ms) were started on beta-blocker therapy at a median age of 14 years (interquartile range: 8 to 32 years). The QTc shortening with propranolol was significantly greater than with other beta-blockers in the total cohort and in the subset with QTc480 ms. None of the asymptomatic patients had BCEs. Among symptomatic patients (n = 101), 15 had BCEs (all syncopes). The QTc shortening was significantly less pronounced among patients with BCEs. There was a greater risk of BCEs for symptomatic patients initiated on metoprolol compared to users of the other 2 beta-blockers combined, after adjustment for genotype (odds ratio: 3.95, 95% confidence interval: 1.2 to 13.1, p = 0.025). Kaplan-Meier analysis showed a significantly lower event-free survival for symptomatic patients receiving metoprolol compared to propranolol/nadolol.Propranolol has a significantly better QTc shortening effect compared to metoprolol and nadolol, especially in patients with prolonged QTc. Propranolol and nadolol are equally effective, whereas symptomatic patients started on metoprolol are at a significantly higher risk for BCEs. Metoprolol should not be used for symptomatic LQT1 and LQT2 patients.

Published
2012

19. A meta-analysis of genome-wide association studies of the electrocardiographic early repolarization pattern

Author

Mika Kähönen, Norman Klopp, Moritz F. Sinner, Eimo Martens, Annamaria Iorio, Barbara Thorand, M. Juhani Junttila, Peter Lichtner, Jani T. Tikkanen, H.-Erich Wichmann, Thomas Meitinger, Christian Hengstenberg, Stefan Kääb, Martina Müller-Nurasyid, Jorma Viikari, Kimmo Porthan, Rebecca R. Cooper, Faisal M. Merchant, Gina M. Peloso, Siegfried Perz, Christa Meisinger, Sheila Ulivi, Heikki V. Huikuri, A. Catharina Brockhaus, Terho Lehtimäki, Christopher J. O'Donnell, Arto Pietilä, Britt M. Beckmann, Markku S. Nieminen, Peter A. Noseworthy, Patrick T. Ellinor, Christopher Newton-Cheh, Annette Peters, Lasse Oikarinen, Shih-Jen Hwang, Olli T. Raitakari, Paolo Gasparini, Aki S. Havulinna, Gianfranco Sinagra, Wibke Reinhard, Leo-Pekka Lyytikäinen, Veikko Salomaa, Kaisa Silander, Maarit A. Laaksonen, M. F., Sinner, K., Porthan, P. A., Noseworthy, A. S., Havulinna, J., Tikkanen, M., Müller Nurasyid, G., Peloso, S., Ulivi, B. M., Beckmann, A. C., Brockhau, R. R., Cooper, Gasparini, Paolo, C., Hengstenberg, S., Hwang, A., Iorio, M. J., Junttila, N., Klopp, M., Kähönen, M. A., Laaksonen, T., Lehtimäki, P., Lichtner, L., Lyytikäinen, E., Marten, C., Meisinger, T., Meitinger, F. M., Merchant, M. S., Nieminen, A., Peter, A., Pietilä, S., Perz, L., Oikarinen, O., Raitakari, W., Reinhard, K., Silander, B., Thorand, H., Wichmann, Sinagra, Gianfranco, J., Viikari, C. J., O'Donnell, P. T., Ellinor, H. V., Huikuri, S., Kääb, C., Newton Cheh, and V., Salomaa

Subjects
Male, medicine.medical_specialty, Single-nucleotide polymorphism, Genome-wide association study, early repolarization, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Article, sudden cardiac death, 03 medical and health sciences, Electrocardiography, 0302 clinical medicine, Framingham Heart Study, Heart Conduction System, Risk Factors, Physiology (medical), Internal medicine, Genetic model, medicine, Humans, Genetic Predisposition to Disease, 030304 developmental biology, Genetic association, 0303 health sciences, business.industry, Arrhythmias, Cardiac, Odds ratio, ta3121, mutations, Confidence interval, genome-wide association, 3. Good health, Death, Sudden, Cardiac, Phenotype, Meta-analysis, Mutation, Female, mutation, Cardiology and Cardiovascular Medicine, business, Demography, Genome-Wide Association Study
Abstract

Background The early repolarization pattern (ERP) is common and associated with risk of sudden cardiac death. ERP is heritable, and mutations have been described in syndromatic cases. Objective To conduct a meta-analysis of genome-wide association studies to identify common genetic variants influencing ERP. Methods We ascertained ERP on the basis of electrocardiograms in 3 large community-based cohorts from Europe and the United States: the Framingham Heart Study, the Health 2000 Study, and the KORA F4 Study. We analyzed genome-wide association studies in participants with and without ERP by logistic regression assuming an additive genetic model and meta-analyzed individual cohort results. We then sought to strengthen support for findings that reached P ≤ 1 × 10 −5 in independent individuals by direct genotyping or in-silico analysis of genome-wide data. We meta-analyzed the results from both stages. Results Of 7482 individuals in the discovery stage, 452 showed ERP (ERP positive: mean age 46.9 ± 8.9 years, 30.3% women; ERP negative: 47.5 ± 9.4 years, 54.2% women). After meta-analysis, 8 single nucleotide polymorphisms reached P ≤ 1 × 10 −5 : The most significant finding was intergenic rs11653989 (odds ratio 0.47; 95% confidence interval 0.36–0.61; P = 6.9 × 10 −9 ). The most biologically relevant finding was intronic to KCND3: rs17029069 (odds ratio 1.46; 95% confidence interval 1.25–1.69; P = 8.5 × 10 −7 ). In the replication step (7151 individuals), none of the 8 variants replicated, and combined meta-analysis results failed to reach genome-wide significance. Conclusions In a genome-wide association study, we were not able to reliably identify genetic variants predisposing to ERP, presumably due to insufficient statistical power and phenotype heterogeneity. The reported heritability of ERP warrants continued investigation in larger well-phenotyped populations.

Published
2012

20. Genome-wide association study of PR interval

Author

Siegfried Perz, Thomas J. Wang, Vilmundur Gudnason, Thomas Meitinger, Elsayed Z. Soliman, Eric Boerwinkle, Bertram Müller-Myhsok, Moritz F. Sinner, Nona Sotoodehnia, Gonçalo R. Abecasis, Dan E. Arking, Daniel Levy, W. H. Linda Kao, Renate B. Schnabel, Jerome I. Rotter, Stefan Kääb, Fernando Rivadeneira, David R. Van Wagoner, Joshua C. Bis, Kirill V. Tarasov, Gudny Eiriksdottir, Ramachandran S. Vasan, Christopher Newton-Cheh, David Schlessinger, Jan A. Kors, Josef Coresh, Kristin D. Marciante, H.-Erich Wichmann, Martina Müller, Thor Aspelund, Bruno H. Stricker, Alvaro Alonso, Samer S. Najjar, Germaine C. Verwoert, Man Li, Britt M. Beckmann, Jared W. Magnani, Kathryn L. Lunetta, Edward G. Lakatta, Serena Sanna, Lenore J. Launer, Albert V. Smith, Emelia J. Benjamin, Cornelia M. van Duijn, Kenneth Rice, Steven A. Lubitz, Patrick T. Ellinor, Arne Pfeufer, Charlotte van Noord, Jonathan D. Smith, Albert Hofman, Christian Gieger, Jacqueline C.M. Witteman, Martin G. Larson, Manuela Uda, Anna Köttgen, Susan R. Heckbert, André G. Uitterlinden, Georg Ehret, Bruce M. Psaty, John Barnard, Tamara B. Harris, Wiebke Sauter, Aravinda Chakravarti, Mina K. Chung, Epidemiology, Intensive Care, Internal Medicine, and Medical Informatics

Subjects
Male, Candidate gene, Population, voltage gated sodium channel, Genome-wide association study, Locus (genetics), 030204 cardiovascular system & hematology, Biology, Article, Cohort Studies, quantitative trait, 03 medical and health sciences, Rotterdam Study, Electrocardiography, 0302 clinical medicine, Meta-Analysis as Topic, Heart Conduction System, Atrial Fibrillation, Genetics, medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, PR interval, education, 030304 developmental biology, Genetic association, Aged, developmental genes, 0303 health sciences, education.field_of_study, genome-wide association study, PQ interval, Atrial fibrillation, medicine.disease, Genetic Loci, cardiovascular system, Female
Abstract

The electrocardiographic PR interval reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation (AF). To identify underlying common genetic variation, we meta-analyzed genome-wide association results for PR interval from seven community-based studies of European-ancestry individuals in the CHARGE consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N=28,517). Statistically significant loci (P

Published
2009

21. Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation

Author

Stefan Kääb, Brian S. Donahue, Calum A. MacRae, Britt M. Beckmann, Jeremy N. Ruskin, Gerhard Steinbeck, Renate B. Schnabel, Dawood Darbar, Thomas Meitinger, Patrick T. Ellinor, Subbarao Choudry, Moritz F. Sinner, Daniel Levy, Jan Heeringa, Seiko Makino, Dan M. Roden, André G. Uitterlinden, Prince J. Kannankeril, Siegfried Perz, Annette Wacker, Kathryn L. Lunetta, Emelia J. Benjamin, Christopher Newton-Cheh, Arne Pfeufer, Jacqueline C.M. Witteman, Martin G. Larson, Albert Schömig, Charlotte van Noord, Josée Dupuis, H.-Erich Wichmann, Epidemiology, and Internal Medicine

Subjects
Male, medicine.medical_specialty, Genotype, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Rotterdam Study, Framingham Heart Study, Clinical Research, Risk Factors, Internal medicine, Atrial Fibrillation, medicine, Humans, Genetic Predisposition to Disease, Aged, Genetics, Framingham Risk Score, business.industry, Case-control study, Genetic Variation, Atrial fibrillation, Odds ratio, Middle Aged, medicine.disease, Confidence interval, Case-Control Studies, Female, Chromosomes, Human, Pair 4, Cardiology and Cardiovascular Medicine, business, Genome-Wide Association Study
Abstract

Aims A recent genome-wide association study identified a haplotype block on chromosome 4q25 associated with atrial fibrillation (AF). We sought to replicate this association in four independent cohorts. Methods and results The Framingham Heart Study and Rotterdam Study are community-based longitudinal studies. The Vanderbilt AF Registry and German AF Network (AFNet) are case–control studies. Participants with AF ( n = 3508) were more likely to be male and were older than referent participants ( n = 12 173; Framingham 82 ± 10 vs. 71 ± 13 years; Rotterdam 73 ± 8 vs. 69 ± 9 years; Vanderbilt 54 ± 14 vs. 57 ± 14 years; AFNet 62 ± 12 vs. 49 ± 14 years). Single nucleotide polymorphism (SNP) rs2200733 was associated with AF in all four cohorts, with odds ratios (ORs) ranging from 1.37 in Rotterdam [95% confidence interval (CI) 1.18–1.59; P = 3.1 × 10−5] to 2.52 in AFNet (95% CI 2.22–2.8; P = 1.8 × 10−49). There also was a significant association between AF and rs10033464 in Framingham (OR 1.34; 95% CI 1.03–1.75; P = 0.031) and AFNet (OR 1.30; 95% CI 1.13–1.51; P = 0.0002), but not Vanderbilt (OR 1.16; 95% CI 0.86–1.56; P = 0.33). A meta-analysis of the current and prior AF studies revealed an OR of 1.90 (95% CI 1.60–2.26; P = 3.3 × 10−13) for rs2200733 and of 1.36 (95% CI 1.26–1.47; P = 6.7 × 10−15) for rs10033464. Conclusion The non-coding SNPs rs2200733 and rs10033464 are strongly associated with AF in four cohorts of European descent. These results confirm the significant relations between AF and intergenic variants on chromosome 4.

Published
2009

22. Baseline values and sotalol-induced changes of ventricular repolarization duration, heterogeneity, and instability in patients with a history of drug-induced torsades de pointes

Author

Anthony A. Fossa, Scott McNitt, Jean-Philippe Couderc, Xiaojuan Xia, Stefan Kääb, Wojciech Zareba, Martin Hinterseer, Slava Polonsky, and Britt M. Beckmann

Subjects
Drug, Male, medicine.medical_specialty, Ventricular Repolarization, media_common.quotation_subject, Context (language use), Torsades de pointes, QT interval, Electrocardiography, Torsades de Pointes, Internal medicine, medicine, Ventricular Dysfunction, Repolarization, Humans, Pharmacology (medical), cardiovascular diseases, media_common, Pharmacology, medicine.diagnostic_test, business.industry, Sotalol, Middle Aged, medicine.disease, Anesthesia, Cardiology, Female, business, Anti-Arrhythmia Agents, medicine.drug
Abstract

The authors investigated whether computerized parameters quantifying ventricular repolarization delay, heterogeneity, and instability characterize individuals who developed drug-induced Torsades de Pointes. Assessing an individual's propensity to Torsades de Pointes when exposed to a QT-prolonging drug is challenging because baseline QT prolongation has limited predictive value. Five-minute digital 12-lead electrocardiograms were acquired at baseline and after a sotalol challenge in 16 patients who had a history of Torsades de Pointes in the context of a QT-prolonging drug and 17 patients who did not have such history. Computerized measurements of QTc, T peak to T end intervals (TpTe), TpTe/QTc, and QT variability were implemented, and novel quantifiers of ventricular repolarization heterogeneity from the early (ERD) and late (LRD) part of the T wave were investigated. Compared with electrocardiograms of patients without a history of Torsades de Pointes, the baseline electrocardiograms of patients with a history of Torsades de Pointes had a longer QTc and an increased repolarization heterogeneity of the early part of the T wave (ERD30%: 44 +/- 13 vs 35 +/- 8 ms, P = .02). On sotalol, the electrocardiograms from individuals with Torsades de Pointes revealed a delay of the terminal part of the T wave that was not present in patients without Torsades de Pointes (TpTe: 27 +/- 40 vs -2 +/- 21 ms, P = .02; LRD70%: 20 +/- 29 vs 2 +/- 4 ms, P = .04). Results suggest that the electrocardiogram abnormalities characterizing patients with a history of Torsades de Pointes are (1) an increased repolarization heterogeneity at baseline and (2) a sotalol-induced prolongation of the terminal part of the T wave.

Published
2008

23. Seizures on hearing the alarm clock

Author

Britt M. Beckmann, Stefan Kääb, Soheyl Noachtar, Christian Vollmar, and Berend Feddersen

Subjects
Adult, medicine.medical_specialty, ERG1 Potassium Channel, Alarm clock, business.industry, Electroencephalography, General Medicine, Audiology, Ether-A-Go-Go Potassium Channels, law.invention, Surgery, Acoustic Stimulation, law, Seizures, Mutation, medicine, Humans, Female, business
Published
2007

24. Dual inheritance of sudden death from cardiovascular causes

Author

Stefan Kääb, Arthur A.M. Wilde, Britt M. Beckmann, Amsterdam Cardiovascular Sciences, and Cardiology

Subjects
Male, Heterozygote, medicine.medical_specialty, Adolescent, business.industry, Ryanodine Receptor Calcium Release Channel, General Medicine, DUAL (cognitive architecture), Catecholaminergic polymorphic ventricular tachycardia, medicine.disease, Sudden death, Pedigree, Long QT Syndrome, Inheritance (object-oriented programming), Death, Sudden, Cardiac, Internal medicine, KCNQ1 Potassium Channel, Tachycardia, Ventricular, cardiovascular system, medicine, Cardiology, Humans, Female, business, Genes, Dominant
Abstract

The long-QT syndrome and catecholaminergic polymorphic ventricular tachycardia are the most common inherited cardiac channelopathies. These authors identified the coexistence of the two diseases in one family. During the past 30 years, nine members have died suddenly between 7 and 40 years of age.

Published
2008

25. Erratum: Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death

Author

Connie R. Bezzina, Kanae Hasegawa, Tohru Minamino, Peter Weeke, Rachel Bastiaenen, Jean-Jacques Schott, Rianne Wolswinkel, Olivier Lantieri, Vincent M. Christoffels, Simon Lecointe, Wataru Shimizu, Véronique Fressart, Richard Redon, Philippe Froguel, Lia Crotti, Charles Antzelevitch, Morten S. Olesen, Manfred Gessler, Stéphanie Chatel, Dan M. Roden, Beverley Balkau, Arie O. Verkerk, Britt M. Beckmann, Jade Violleau, Stéphane Bézieau, Arthur A.M. Wilde, Ruben Coronel, David Weber, Christian Dina, Hiroshi Watanabe, Pierre Lindenbaum, Stefan Kääb, Julien Barc, Aurore Despres, Peter J. Schwartz, Eric Charpentier, Carol Ann Remme, Akihiko Nogami, Minoru Horie, Margherita Torchio, Sven Zumhagen, Françoise Gros, Naomasa Makita, Florence Kyndt, Cornelia Wiese, Vincent Probst, Naoto Endo, Takeshi Aiba, Hervé Le Marec, Susan Bartkowiak, Bas J. Boukens, Seiko Ohno, Eric Schulze-Bahr, Pascale Guicheney, Antoine Leenhardt, Vincent Portero, Hanno L. Tan, Yuka Mizusawa, Jacob Tfelt-Hansen, Elijah R. Behr, Floriane Simonet, Jean-Baptiste Gourraud, and Federica Dagradi

Subjects
Genetics, medicine, Biology, HEY2, medicine.disease, Sudden cardiac death, Brugada syndrome, Rare disease
Published
2013

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