89 results on '"Barc, J"'
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2. Canola meal or soybean meal as protein source and the effect of microencapsulated sodium butyrate supplementation in calf starter mixture. II. Development of the gastrointestinal tract
- Author
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Burakowska, K., Penner, G.B., Flaga, J., Przybyło, M., Barć, J., Wojciechowska-Puchałka, J., Wojtysiak, D., Kowalski, Z.M., and Górka, P.
- Published
- 2021
- Full Text
- View/download PDF
3. Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry
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Crotti, L, Spazzolini, C, Nyegaard, M, Overgaard, M, Kotta, M, Dagradi, F, Sala, L, Aiba, T, Ayers, M, Baban, A, Barc, J, Beach, C, Behr, E, Bos, J, Cerrone, M, Covi, P, Cuneo, B, Denjoy, I, Donner, B, Elbert, A, Eliasson, H, Etheridge, S, Fukuyama, M, Girolami, F, Hamilton, R, Horie, M, Iascone, M, Jaimez, J, Jensen, H, Kannankeril, P, Kaski, J, Makita, N, Muñoz-Esparza, C, Odland, H, Ohno, S, Papagiannis, J, Porretta, A, Prandstetter, C, Probst, V, Robyns, T, Rosenthal, E, Rosés-Noguer, F, Sekarski, N, Singh, A, Spentzou, G, Stute, F, Tfelt-Hansen, J, Till, J, Tobert, K, Vinocur, J, Webster, G, Wilde, A, Wolf, C, Ackerman, M, Schwartz, P, Crotti L., Spazzolini C., Nyegaard M., Overgaard M. T., Kotta M. C., Dagradi F., Sala L., Aiba T., Ayers M. D., Baban A., Barc J., Beach C. M., Behr E. R., Bos J. M., Cerrone M., Covi P., Cuneo B., Denjoy I., Donner B., Elbert A., Eliasson H., Etheridge S. P., Fukuyama M., Girolami F., Hamilton R., Horie M., Iascone M., Jaimez J. J., Jensen H. K., Kannankeril P. J., Kaski J. P., Makita N., Muñoz-Esparza C., Odland H. H., Ohno S., Papagiannis J., Porretta A. P., Prandstetter C., Probst V., Robyns T., Rosenthal E., Rosés-Noguer F., Sekarski N., Singh A., Spentzou G., Stute F., Tfelt-Hansen J., Till J., Tobert K. E., Vinocur J. M., Webster G., Wilde A. A. M., Wolf C. M., Ackerman M. J., Schwartz P. J., Crotti, L, Spazzolini, C, Nyegaard, M, Overgaard, M, Kotta, M, Dagradi, F, Sala, L, Aiba, T, Ayers, M, Baban, A, Barc, J, Beach, C, Behr, E, Bos, J, Cerrone, M, Covi, P, Cuneo, B, Denjoy, I, Donner, B, Elbert, A, Eliasson, H, Etheridge, S, Fukuyama, M, Girolami, F, Hamilton, R, Horie, M, Iascone, M, Jaimez, J, Jensen, H, Kannankeril, P, Kaski, J, Makita, N, Muñoz-Esparza, C, Odland, H, Ohno, S, Papagiannis, J, Porretta, A, Prandstetter, C, Probst, V, Robyns, T, Rosenthal, E, Rosés-Noguer, F, Sekarski, N, Singh, A, Spentzou, G, Stute, F, Tfelt-Hansen, J, Till, J, Tobert, K, Vinocur, J, Webster, G, Wilde, A, Wolf, C, Ackerman, M, Schwartz, P, Crotti L., Spazzolini C., Nyegaard M., Overgaard M. T., Kotta M. C., Dagradi F., Sala L., Aiba T., Ayers M. D., Baban A., Barc J., Beach C. M., Behr E. R., Bos J. M., Cerrone M., Covi P., Cuneo B., Denjoy I., Donner B., Elbert A., Eliasson H., Etheridge S. P., Fukuyama M., Girolami F., Hamilton R., Horie M., Iascone M., Jaimez J. J., Jensen H. K., Kannankeril P. J., Kaski J. P., Makita N., Muñoz-Esparza C., Odland H. H., Ohno S., Papagiannis J., Porretta A. P., Prandstetter C., Probst V., Robyns T., Rosenthal E., Rosés-Noguer F., Sekarski N., Singh A., Spentzou G., Stute F., Tfelt-Hansen J., Till J., Tobert K. E., Vinocur J. M., Webster G., Wilde A. A. M., Wolf C. M., Ackerman M. J., and Schwartz P. J.
- Abstract
Aims: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. Methods and results: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P =. 001) and sudden death (9% vs. 27%; P =. 008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. Conclusion: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator.
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- 2023
4. Population-specific and cross-ancestry genome-wide association study identifies shared genetic architecture and 6 new risk loci including CAMK2D associated for Brugada syndrome
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Makita, N, primary, Ishikawa, T, additional, Masuda, T, additional, Hachiya, T, additional, Dina, C, additional, Simonet, F, additional, Tank, M W T, additional, Wilde, A A, additional, Redon, R, additional, Bezzina, C R, additional, Tanaka, T, additional, Barc, J, additional, Okada, Y, additional, and Schott, J J, additional
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- 2023
- Full Text
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5. Modeling familial sinus node dysfunction with a large intergenic deletion between PITX2 and ANK2 using iPS cell-derived sinoatrial nodal-like cardiomyocytes
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Aizawa, T, primary, Makiyama, T, additional, Murata, H, additional, Takaki, T, additional, Baudic, M, additional, Gao, J, additional, Imamura, T, additional, Ohno, S, additional, Yoshida, Y, additional, Shimizu, W, additional, Makita, N, additional, Barc, J, additional, Schott, J J, additional, Horie, M, additional, and Kimura, T, additional
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- 2023
- Full Text
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6. Non-coding deletion induces 3D chromatin remodelling and PITX2 expression dysregulation associated with a syndromic cardiac disorder
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Baudic, M., primary, Murata, H., additional, Bosada, F., additional, Souto Melo, U., additional, Aizawa, T., additional, Guedon, A., additional, Lindenbaum, P., additional, Gourraud, J.-B., additional, Makita, N., additional, Mundlos, S., additional, Christoffels, V.M., additional, Makiyama, T., additional, Probst, V., additional, Schott, J.-J., additional, and Barc, J., additional
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- 2023
- Full Text
- View/download PDF
7. Cadherin 2-Related Arrhythmogenic Cardiomyopathy: Prevalence and Clinical Features
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Ghidoni, A, Elliott, P, Syrris, P, Calkins, H, James, C, Judge, D, Murray, B, Barc, J, Probst, V, Schott, J, Song, J, Hauer, R, Hoorntje, E, Van Tintelen, J, Schulze-Bahr, E, Hamilton, R, Mittal, K, Semsarian, C, Behr, E, Ackerman, M, Basso, C, Parati, G, Gentilini, D, Kotta, M, Mayosi, B, Schwartz, P, Crotti, L, Ghidoni A., Elliott P. M., Syrris P., Calkins H., James C. A., Judge D. P., Murray B., Barc J., Probst V., Schott J. J., Song J. -P., Hauer R. N. W., Hoorntje E. T., Van Tintelen J. P., Schulze-Bahr E., Hamilton R. M., Mittal K., Semsarian C., Behr E. R., Ackerman M. J., Basso C., Parati G., Gentilini D., Kotta M. -C., Mayosi B. M., Schwartz P. J., Crotti L., Ghidoni, A, Elliott, P, Syrris, P, Calkins, H, James, C, Judge, D, Murray, B, Barc, J, Probst, V, Schott, J, Song, J, Hauer, R, Hoorntje, E, Van Tintelen, J, Schulze-Bahr, E, Hamilton, R, Mittal, K, Semsarian, C, Behr, E, Ackerman, M, Basso, C, Parati, G, Gentilini, D, Kotta, M, Mayosi, B, Schwartz, P, Crotti, L, Ghidoni A., Elliott P. M., Syrris P., Calkins H., James C. A., Judge D. P., Murray B., Barc J., Probst V., Schott J. J., Song J. -P., Hauer R. N. W., Hoorntje E. T., Van Tintelen J. P., Schulze-Bahr E., Hamilton R. M., Mittal K., Semsarian C., Behr E. R., Ackerman M. J., Basso C., Parati G., Gentilini D., Kotta M. -C., Mayosi B. M., Schwartz P. J., and Crotti L.
- Abstract
Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the right and left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants in the nondesmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM. Methods: A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of CDH2 was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of CDH2-positive probands, and clinical evaluation was performed. Results: Genetic screening of CDH2 led to the identification of 7 rare variants: 5, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in CDH2 were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most CDH2-positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and sudden cardiac death occurred in 5/9 (56%). Conclusions: In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with CDH2 pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of CDH2-ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.
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- 2021
8. Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls
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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, Walsh R., Lahrouchi N., Tadros R., Kyndt F., Glinge C., Postema P. G., Amin A. S., Nannenberg E. A., Ware J. S., Whiffin N., Mazzarotto F., Skoric-Milosavljevic D., Krijger C., Arbelo E., Babuty D., Barajas-Martinez H., Beckmann B. M., Bezieau S., Bos J. M., 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. T., Ortuno C. G., Giustetto C., Gourraud J. -B., Hazeki D., Horie M., Ishikawa T., Itoh H., Kaneko Y., Kanters J. K., Kimoto H., Kotta M. -C., Krapels I. P. C., Kurabayashi M., Lazarte J., Leenhardt A., Loeys B. L., Lundin C., Makiyama T., Mansourati J., Martins R. P., Mazzanti A., Morner S., Napolitano C., Ohkubo K., Papadakis M., Rudic B., Molina M. S., Sacher F., Sahin H., Sarquella-Brugada G., Sebastiano R., Sharma S., Sheppard M. N., Shimamoto K., Shoemaker M. B., Stallmeyer B., Steinfurt J., Tanaka Y., Tester D. J., Usuda K., van der Zwaag P. A., Van Dooren S., Van Laer L., Winbo A., Winkel B. G., Yamagata K., Zumhagen S., Volders P. G. A., Lubitz S. A., Antzelevitch C., Platonov P. G., Odening K. E., Roden D. M., Roberts J. D., Skinner J. R., Tfelt-Hansen J., van den Berg M. P., Olesen M. S., Lambiase P. D., Borggrefe M., Hayashi K., Rydberg A., Nakajima T., Yoshinaga M., Saenen J. B., Kaab S., Brugada P., Robyns T., Giachino D. F., Ackerman M. J., Brugada R., Brugada J., Gimeno J. R., Hasdemir C., Guicheney P., Priori S. G., Schulze-Bahr E., Makita N., Schwartz P. J., Shimizu W., Aiba T., Schott J. -J., Redon R., Ohno S., Probst V., Arnaout A. A., Amelot M., Anselme F., Billon O., Defaye P., Dupuis J. -M., Jesel L., Laurent G., Maury P., Pasquie J. -L., Wiart F., Behr E. R., Barc J., Bezzina C. R., 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, Walsh R., Lahrouchi N., Tadros R., Kyndt F., Glinge C., Postema P. G., Amin A. S., Nannenberg E. A., Ware J. S., Whiffin N., Mazzarotto F., Skoric-Milosavljevic D., Krijger C., Arbelo E., Babuty D., Barajas-Martinez H., Beckmann B. M., Bezieau S., Bos J. M., 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. T., Ortuno C. G., Giustetto C., Gourraud J. -B., Hazeki D., Horie M., Ishikawa T., Itoh H., Kaneko Y., Kanters J. K., Kimoto H., Kotta M. -C., Krapels I. P. C., Kurabayashi M., Lazarte J., Leenhardt A., Loeys B. L., Lundin C., Makiyama T., Mansourati J., Martins R. P., Mazzanti A., Morner S., Napolitano C., Ohkubo K., Papadakis M., Rudic B., Molina M. S., Sacher F., Sahin H., Sarquella-Brugada G., Sebastiano R., Sharma S., Sheppard M. N., Shimamoto K., Shoemaker M. B., Stallmeyer B., Steinfurt J., Tanaka Y., Tester D. J., Usuda K., van der Zwaag P. A., Van Dooren S., Van Laer L., Winbo A., Winkel B. G., Yamagata K., Zumhagen S., Volders P. G. A., Lubitz S. A., Antzelevitch C., Platonov P. G., Odening K. E., Roden D. M., Roberts J. D., Skinner J. R., Tfelt-Hansen J., van den Berg M. P., Olesen M. S., Lambiase P. D., Borggrefe M., Hayashi K., Rydberg A., Nakajima T., Yoshinaga M., Saenen J. B., Kaab S., Brugada P., Robyns T., Giachino D. F., Ackerman M. J., Brugada R., Brugada J., Gimeno J. R., Hasdemir C., Guicheney P., Priori S. G., Schulze-Bahr E., Makita N., Schwartz P. J., Shimizu W., Aiba T., Schott J. -J., Redon R., Ohno S., Probst V., Arnaout A. A., Amelot M., Anselme F., Billon O., Defaye P., Dupuis J. -M., Jesel L., Laurent G., Maury P., Pasquie J. -L., Wiart F., Behr E. R., Barc J., and Bezzina C. R.
- 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 × 10−18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 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.
- Published
- 2021
9. Syndromic cardiac disorder is associated with a non-coding deletion that induces a 3D chromatin remodeling and PITX2 expression dysregulation
- Author
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Baudic, M, primary, Murata, H, additional, Bosada, F M, additional, Souto Melo, U, additional, Aizawa, T, additional, Guedon, A, additional, Lindenbaum, P, additional, Gourraud, J B, additional, Makita, N, additional, Mundlos, S, additional, Christoffels, V M, additional, Makiyama, T, additional, Probst, V, additional, Schott, J J, additional, and Barc, J, additional
- Published
- 2022
- Full Text
- View/download PDF
10. Author Correction: Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility (Nature Genetics, (2022), 54, 3, (232-239), 10.1038/s41588-021-01007-6)
- Author
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Julien Barc, Barc, J, Tadros, R, Glinge, C, Chiang, D, Jouni, M, Simonet, F, Jurgens, S, Baudic, M, Nicastro, M, Potet, F, Offerhaus, J, Walsh, R, Hoan Choi, S, Verkerk, A, Mizusawa, Y, Anys, S, Minois, D, Arnaud, M, Duchateau, J, Wijeyeratne, Y, Muir, A, Papadakis, M, Castelletti, S, Torchio, M, Gil Ortuño, C, Lacunza, J, Giachino, D, Cerrato, N, Martins, R, Campuzano, O, Van Dooren, S, Thollet, A, Kyndt, F, Mazzanti, A, Clémenty, N, Bisson, A, Corveleyn, A, Stallmeyer, B, Dittmann, S, Saenen, J, Noël, A, Honarbakhsh, S, Rudic, B, Marzak, H, Rowe, M, Federspiel, C, Le Page, S, Placide, L, Milhem, A, Barajas-Martinez, H, Beckmann, B, Krapels, I, Steinfurt, J, Gregers Winkel, B, Jabbari, R, Shoemaker, M, Boukens, B, Škorić-Milosavljević, D, Bikker, H, Manevy, F, Lichtner, P, Ribasés, M, Meitinger, T, Müller-Nurasyid, M, Group, K, Veldink, J, van den Berg, L, Van Damme, P, Cusi, D, Lanzani, C, Rigade, S, Charpentier, E, Baron, E, Bonnaud, S, Lecointe, S, Donnart, A, Le Marec, H, Chatel, S, Karakachoff, M, Bézieau, S, London, B, Tfelt-Hansen, J, Roden, D, Odening, K, Cerrone, M, Chinitz, L, Volders, P, van de Berg, M, Laurent, G, Faivre, L, Antzelevitch, C, Kääb, S, Al Arnaout, A, Dupuis, J, Pasquie, J, Billon, O, Roberts, J, Jesel, L, Borggrefe, M, Lambiase, P, Mansourati, J, Loeys, B, Leenhardt, A, Guicheney, P, Maury, P, Schulze-Bahr, E, Robyns, T, Breckpot, J, Babuty, D, Priori, S, Napolitano, C, Referral Center for inherited cardiac arrhythmia, N, de Asmundis, C, Brugada, P, Brugada, R, Arbelo, E, Brugada, J, Mabo, P, Behar, N, Giustetto, C, Sabater Molina, M, Gimeno, J, Hasdemir, C, Schwartz, P, Crotti, L, Mckeown, P, Sharma, S, Behr, E, Haissaguerre, M, Sacher, F, Rooryck, C, Tan, H, Remme, C, Postema, P, Delmar, M, Ellinor, P, Lubitz, S, Gourraud, J, Tanck, M, L. George Jr., A, Macrae, C, Burridge, P, Dina, C, Probst, V, Wilde, A, Schott, J, Redon &, R, Bezzina, C, Julien Barc, Rafik Tadros, Charlotte Glinge, David Y. Chiang, Mariam Jouni, Floriane Simonet, Sean J. Jurgens, Manon Baudic, Michele Nicastro, Franck Potet, Joost A. Offerhaus, Roddy Walsh, Seung Hoan Choi, Arie O. Verkerk, Yuka Mizusawa, Soraya Anys, Damien Minois, Marine Arnaud, Josselin Duchateau, Yanushi D. Wijeyeratne, Alison Muir, Michael Papadakis, Silvia Castelletti, Margherita Torchio, Cristina Gil Ortuño, Javier Lacunza, Daniela F. Giachino, Natascia Cerrato, Raphaël P. Martins, Oscar Campuzano, Sonia Van Dooren, Aurélie Thollet, Florence Kyndt, Andrea Mazzanti, Nicolas Clémenty, Arnaud Bisson, Anniek Corveleyn, Birgit Stallmeyer, Sven Dittmann, Johan Saenen, Antoine Noël, Shohreh Honarbakhsh, Boris Rudic, Halim Marzak, Matthew K. Rowe, Claire Federspiel, Sophie Le Page, Leslie Placide, Antoine Milhem, Hector Barajas-Martinez, Britt-Maria Beckmann, Ingrid P. Krapels, Johannes Steinfurt, Bo Gregers Winkel, Reza Jabbari, Moore B. Shoemaker, Bas J. Boukens, Doris Škorić-Milosavljević, Hennie Bikker, Federico Manevy, Peter Lichtner, Marta Ribasés, Thomas Meitinger, Martina Müller-Nurasyid, KORA-Study Group, Jan H. Veldink, Leonard H. van den Berg, Philip Van Damme, Daniele Cusi, Chiara Lanzani, Sidwell Rigade, Eric Charpentier, Estelle Baron, Stéphanie Bonnaud, Simon Lecointe, Audrey Donnart, Hervé Le Marec, Stéphanie Chatel, Matilde Karakachoff, Stéphane Bézieau, Barry London, Jacob Tfelt-Hansen, Dan Roden, Katja E. Odening, Marina Cerrone, Larry A. Chinitz, Paul G. Volders, Maarten P. van de Berg, Gabriel Laurent, Laurence Faivre, Charles Antzelevitch, Stefan Kääb, Alain Al Arnaout, Jean-Marc Dupuis, Jean-Luc Pasquie, Olivier Billon, Jason D. Roberts, Laurence Jesel, Martin Borggrefe, Pier D. Lambiase, Jacques Mansourati, Bart Loeys, Antoine Leenhardt, Pascale Guicheney, Philippe Maury, Eric Schulze-Bahr, Tomas Robyns, Jeroen Breckpot, Dominique Babuty, Silvia G. Priori, Carlo Napolitano, Nantes Referral Center for inherited cardiac arrhythmia, Carlo de Asmundis, Pedro Brugada, Ramon Brugada, Elena Arbelo, Josep Brugada, Philippe Mabo, Nathalie Behar, Carla Giustetto, Maria Sabater Molina, Juan R. Gimeno, Can Hasdemir, Peter J. Schwartz, Lia Crotti, Pascal P. McKeown, Sanjay Sharma, Elijah R. Behr, Michel Haissaguerre, Frédéric Sacher, Caroline Rooryck, Hanno L. Tan, Carol A. Remme, Pieter G. Postema, Mario Delmar, Patrick T. Ellinor, Steven A. Lubitz, Jean-Baptiste Gourraud, Michael W. Tanck, Alfred L. George Jr., Calum A. MacRae, Paul W. Burridge, Christian Dina, Vincent Probst, Arthur A. Wilde, Jean-Jacques Schott, Richard Redon &, Connie R. Bezzina, Julien Barc, Barc, J, Tadros, R, Glinge, C, Chiang, D, Jouni, M, Simonet, F, Jurgens, S, Baudic, M, Nicastro, M, Potet, F, Offerhaus, J, Walsh, R, Hoan Choi, S, Verkerk, A, Mizusawa, Y, Anys, S, Minois, D, Arnaud, M, Duchateau, J, Wijeyeratne, Y, Muir, A, Papadakis, M, Castelletti, S, Torchio, M, Gil Ortuño, C, Lacunza, J, Giachino, D, Cerrato, N, Martins, R, Campuzano, O, Van Dooren, S, Thollet, A, Kyndt, F, Mazzanti, A, Clémenty, N, Bisson, A, Corveleyn, A, Stallmeyer, B, Dittmann, S, Saenen, J, Noël, A, Honarbakhsh, S, Rudic, B, Marzak, H, Rowe, M, Federspiel, C, Le Page, S, Placide, L, Milhem, A, Barajas-Martinez, H, Beckmann, B, Krapels, I, Steinfurt, J, Gregers Winkel, B, Jabbari, R, Shoemaker, M, Boukens, B, Škorić-Milosavljević, D, Bikker, H, Manevy, F, Lichtner, P, Ribasés, M, Meitinger, T, Müller-Nurasyid, M, Group, K, Veldink, J, van den Berg, L, Van Damme, P, Cusi, D, Lanzani, C, Rigade, S, Charpentier, E, Baron, E, Bonnaud, S, Lecointe, S, Donnart, A, Le Marec, H, Chatel, S, Karakachoff, M, Bézieau, S, London, B, Tfelt-Hansen, J, Roden, D, Odening, K, Cerrone, M, Chinitz, L, Volders, P, van de Berg, M, Laurent, G, Faivre, L, Antzelevitch, C, Kääb, S, Al Arnaout, A, Dupuis, J, Pasquie, J, Billon, O, Roberts, J, Jesel, L, Borggrefe, M, Lambiase, P, Mansourati, J, Loeys, B, Leenhardt, A, Guicheney, P, Maury, P, Schulze-Bahr, E, Robyns, T, Breckpot, J, Babuty, D, Priori, S, Napolitano, C, Referral Center for inherited cardiac arrhythmia, N, de Asmundis, C, Brugada, P, Brugada, R, Arbelo, E, Brugada, J, Mabo, P, Behar, N, Giustetto, C, Sabater Molina, M, Gimeno, J, Hasdemir, C, Schwartz, P, Crotti, L, Mckeown, P, Sharma, S, Behr, E, Haissaguerre, M, Sacher, F, Rooryck, C, Tan, H, Remme, C, Postema, P, Delmar, M, Ellinor, P, Lubitz, S, Gourraud, J, Tanck, M, L. George Jr., A, Macrae, C, Burridge, P, Dina, C, Probst, V, Wilde, A, Schott, J, Redon &, R, Bezzina, C, Julien Barc, Rafik Tadros, Charlotte Glinge, David Y. Chiang, Mariam Jouni, Floriane Simonet, Sean J. Jurgens, Manon Baudic, Michele Nicastro, Franck Potet, Joost A. Offerhaus, Roddy Walsh, Seung Hoan Choi, Arie O. Verkerk, Yuka Mizusawa, Soraya Anys, Damien Minois, Marine Arnaud, Josselin Duchateau, Yanushi D. Wijeyeratne, Alison Muir, Michael Papadakis, Silvia Castelletti, Margherita Torchio, Cristina Gil Ortuño, Javier Lacunza, Daniela F. Giachino, Natascia Cerrato, Raphaël P. Martins, Oscar Campuzano, Sonia Van Dooren, Aurélie Thollet, Florence Kyndt, Andrea Mazzanti, Nicolas Clémenty, Arnaud Bisson, Anniek Corveleyn, Birgit Stallmeyer, Sven Dittmann, Johan Saenen, Antoine Noël, Shohreh Honarbakhsh, Boris Rudic, Halim Marzak, Matthew K. Rowe, Claire Federspiel, Sophie Le Page, Leslie Placide, Antoine Milhem, Hector Barajas-Martinez, Britt-Maria Beckmann, Ingrid P. Krapels, Johannes Steinfurt, Bo Gregers Winkel, Reza Jabbari, Moore B. Shoemaker, Bas J. Boukens, Doris Škorić-Milosavljević, Hennie Bikker, Federico Manevy, Peter Lichtner, Marta Ribasés, Thomas Meitinger, Martina Müller-Nurasyid, KORA-Study Group, Jan H. Veldink, Leonard H. van den Berg, Philip Van Damme, Daniele Cusi, Chiara Lanzani, Sidwell Rigade, Eric Charpentier, Estelle Baron, Stéphanie Bonnaud, Simon Lecointe, Audrey Donnart, Hervé Le Marec, Stéphanie Chatel, Matilde Karakachoff, Stéphane Bézieau, Barry London, Jacob Tfelt-Hansen, Dan Roden, Katja E. Odening, Marina Cerrone, Larry A. Chinitz, Paul G. Volders, Maarten P. van de Berg, Gabriel Laurent, Laurence Faivre, Charles Antzelevitch, Stefan Kääb, Alain Al Arnaout, Jean-Marc Dupuis, Jean-Luc Pasquie, Olivier Billon, Jason D. Roberts, Laurence Jesel, Martin Borggrefe, Pier D. Lambiase, Jacques Mansourati, Bart Loeys, Antoine Leenhardt, Pascale Guicheney, Philippe Maury, Eric Schulze-Bahr, Tomas Robyns, Jeroen Breckpot, Dominique Babuty, Silvia G. Priori, Carlo Napolitano, Nantes Referral Center for inherited cardiac arrhythmia, Carlo de Asmundis, Pedro Brugada, Ramon Brugada, Elena Arbelo, Josep Brugada, Philippe Mabo, Nathalie Behar, Carla Giustetto, Maria Sabater Molina, Juan R. Gimeno, Can Hasdemir, Peter J. Schwartz, Lia Crotti, Pascal P. McKeown, Sanjay Sharma, Elijah R. Behr, Michel Haissaguerre, Frédéric Sacher, Caroline Rooryck, Hanno L. Tan, Carol A. Remme, Pieter G. Postema, Mario Delmar, Patrick T. Ellinor, Steven A. Lubitz, Jean-Baptiste Gourraud, Michael W. Tanck, Alfred L. George Jr., Calum A. MacRae, Paul W. Burridge, Christian Dina, Vincent Probst, Arthur A. Wilde, Jean-Jacques Schott, Richard Redon &, and Connie R. Bezzina
- Abstract
In the version of this article initially published, Federico Manevy’s name appeared with a middle initial in error. The name has been corrected in the HTML and PDF versions of the article.
- Published
- 2022
11. Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility
- Author
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Barc, J, Tadros, R, Glinge, C, Chiang, D, Jouni, M, Simonet, F, Jurgens, S, Baudic, M, Nicastro, M, Potet, F, Offerhaus, J, Walsh, R, Hoan Choi, S, Verkerk, A, Mizusawa, Y, Anys, S, Minois, D, Arnaud, M, Duchateau, J, Wijeyeratne, Y, Muir, A, Papadakis, M, Castelletti, S, Torchio, M, Gil Ortuño, C, Lacunza, J, Giachino, D, Cerrato, N, Martins, R, Campuzano, O, Van Dooren, S, Thollet, A, Kyndt, F, Mazzanti, A, Clémenty, N, Bisson, A, Corveleyn, A, Stallmeyer, B, Dittmann, S, Saenen, J, Noël, A, Honarbakhsh, S, Rudic, B, Marzak, H, Rowe, M, Federspiel, C, Le Page, S, Placide, L, Milhem, A, Barajas-Martinez, H, Beckmann, B, Krapels, I, Steinfurt, J, Gregers Winkel, B, Jabbari, R, Shoemaker, M, Boukens, B, Škorić-Milosavljević, D, Bikker, H, Manevy, F, Lichtner, P, Ribasés, M, Meitinger, T, Müller-Nurasyid, M, Group, K, Veldink, J, van den Berg, L, Van Damme, P, Cusi, D, Lanzani, C, Rigade, S, Charpentier, E, Baron, E, Bonnaud, S, Lecointe, S, Donnart, A, Le Marec, H, Chatel, S, Karakachoff, M, Bézieau, S, London, B, Tfelt-Hansen, J, Roden, D, Odening, K, Cerrone, M, Chinitz, L, Volders, P, van de Berg, M, Laurent, G, Faivre, L, Antzelevitch, C, Kääb, S, Al Arnaout, A, Dupuis, J, Pasquie, J, Billon, O, Roberts, J, Jesel, L, Borggrefe, M, Lambiase, P, Mansourati, J, Loeys, B, Leenhardt, A, Guicheney, P, Maury, P, Schulze-Bahr, E, Robyns, T, Breckpot, J, Babuty, D, Priori, S, Napolitano, C, Referral Center for inherited cardiac arrhythmia, N, de Asmundis, C, Brugada, P, Brugada, R, Arbelo, E, Brugada, J, Mabo, P, Behar, N, Giustetto, C, Sabater Molina, M, Gimeno, J, Hasdemir, C, Schwartz, P, Crotti, L, Mckeown, P, Sharma, S, Behr, E, Haissaguerre, M, Sacher, F, Rooryck, C, Tan, H, Remme, C, Postema, P, Delmar, M, Ellinor, P, Lubitz, S, Gourraud, J, Tanck, M, L. George Jr., A, Macrae, C, Burridge, P, Dina, C, Probst, V, Wilde, A, Schott, J, Redon &, R, Bezzina, C, Julien Barc, Rafik Tadros, Charlotte Glinge, David Y. Chiang, Mariam Jouni, Floriane Simonet, Sean J. Jurgens, Manon Baudic, Michele Nicastro, Franck Potet, Joost A. Offerhaus, Roddy Walsh, Seung Hoan Choi, Arie O. Verkerk, Yuka Mizusawa, Soraya Anys, Damien Minois, Marine Arnaud, Josselin Duchateau, Yanushi D. Wijeyeratne, Alison Muir, Michael Papadakis, Silvia Castelletti, Margherita Torchio, Cristina Gil Ortuño, Javier Lacunza, Daniela F. Giachino, Natascia Cerrato, Raphaël P. Martins, Oscar Campuzano, Sonia Van Dooren, Aurélie Thollet, Florence Kyndt, Andrea Mazzanti, Nicolas Clémenty, Arnaud Bisson, Anniek Corveleyn, Birgit Stallmeyer, Sven Dittmann, Johan Saenen, Antoine Noël, Shohreh Honarbakhsh, Boris Rudic, Halim Marzak, Matthew K. Rowe, Claire Federspiel, Sophie Le Page, Leslie Placide, Antoine Milhem, Hector Barajas-Martinez, Britt-Maria Beckmann, Ingrid P. Krapels, Johannes Steinfurt, Bo Gregers Winkel, Reza Jabbari, Moore B. Shoemaker, Bas J. Boukens, Doris Škorić-Milosavljević, Hennie Bikker, Federico Manevy, Peter Lichtner, Marta Ribasés, Thomas Meitinger, Martina Müller-Nurasyid, KORA-Study Group, Jan H. Veldink, Leonard H. van den Berg, Philip Van Damme, Daniele Cusi, Chiara Lanzani, Sidwell Rigade, Eric Charpentier, Estelle Baron, Stéphanie Bonnaud, Simon Lecointe, Audrey Donnart, Hervé Le Marec, Stéphanie Chatel, Matilde Karakachoff, Stéphane Bézieau, Barry London, Jacob Tfelt-Hansen, Dan Roden, Katja E. Odening, Marina Cerrone, Larry A. Chinitz, Paul G. Volders, Maarten P. van de Berg, Gabriel Laurent, Laurence Faivre, Charles Antzelevitch, Stefan Kääb, Alain Al Arnaout, Jean-Marc Dupuis, Jean-Luc Pasquie, Olivier Billon, Jason D. Roberts, Laurence Jesel, Martin Borggrefe, Pier D. Lambiase, Jacques Mansourati, Bart Loeys, Antoine Leenhardt, Pascale Guicheney, Philippe Maury, Eric Schulze-Bahr, Tomas Robyns, Jeroen Breckpot, Dominique Babuty, Silvia G. Priori, Carlo Napolitano, Nantes Referral Center for inherited cardiac arrhythmia, Carlo de Asmundis, Pedro Brugada, Ramon Brugada, Elena Arbelo, Josep Brugada, Philippe Mabo, Nathalie Behar, Carla Giustetto, Maria Sabater Molina, Juan R. Gimeno, Can Hasdemir, Peter J. Schwartz, Lia Crotti, Pascal P. McKeown, Sanjay Sharma, Elijah R. Behr, Michel Haissaguerre, Frédéric Sacher, Caroline Rooryck, Hanno L. Tan, Carol A. Remme, Pieter G. Postema, Mario Delmar, Patrick T. Ellinor, Steven A. Lubitz, Jean-Baptiste Gourraud, Michael W. Tanck, Alfred L. George Jr., Calum A. MacRae, Paul W. Burridge, Christian Dina, Vincent Probst, Arthur A. Wilde, Jean-Jacques Schott, Richard Redon &, Connie R. Bezzina, Barc, J, Tadros, R, Glinge, C, Chiang, D, Jouni, M, Simonet, F, Jurgens, S, Baudic, M, Nicastro, M, Potet, F, Offerhaus, J, Walsh, R, Hoan Choi, S, Verkerk, A, Mizusawa, Y, Anys, S, Minois, D, Arnaud, M, Duchateau, J, Wijeyeratne, Y, Muir, A, Papadakis, M, Castelletti, S, Torchio, M, Gil Ortuño, C, Lacunza, J, Giachino, D, Cerrato, N, Martins, R, Campuzano, O, Van Dooren, S, Thollet, A, Kyndt, F, Mazzanti, A, Clémenty, N, Bisson, A, Corveleyn, A, Stallmeyer, B, Dittmann, S, Saenen, J, Noël, A, Honarbakhsh, S, Rudic, B, Marzak, H, Rowe, M, Federspiel, C, Le Page, S, Placide, L, Milhem, A, Barajas-Martinez, H, Beckmann, B, Krapels, I, Steinfurt, J, Gregers Winkel, B, Jabbari, R, Shoemaker, M, Boukens, B, Škorić-Milosavljević, D, Bikker, H, Manevy, F, Lichtner, P, Ribasés, M, Meitinger, T, Müller-Nurasyid, M, Group, K, Veldink, J, van den Berg, L, Van Damme, P, Cusi, D, Lanzani, C, Rigade, S, Charpentier, E, Baron, E, Bonnaud, S, Lecointe, S, Donnart, A, Le Marec, H, Chatel, S, Karakachoff, M, Bézieau, S, London, B, Tfelt-Hansen, J, Roden, D, Odening, K, Cerrone, M, Chinitz, L, Volders, P, van de Berg, M, Laurent, G, Faivre, L, Antzelevitch, C, Kääb, S, Al Arnaout, A, Dupuis, J, Pasquie, J, Billon, O, Roberts, J, Jesel, L, Borggrefe, M, Lambiase, P, Mansourati, J, Loeys, B, Leenhardt, A, Guicheney, P, Maury, P, Schulze-Bahr, E, Robyns, T, Breckpot, J, Babuty, D, Priori, S, Napolitano, C, Referral Center for inherited cardiac arrhythmia, N, de Asmundis, C, Brugada, P, Brugada, R, Arbelo, E, Brugada, J, Mabo, P, Behar, N, Giustetto, C, Sabater Molina, M, Gimeno, J, Hasdemir, C, Schwartz, P, Crotti, L, Mckeown, P, Sharma, S, Behr, E, Haissaguerre, M, Sacher, F, Rooryck, C, Tan, H, Remme, C, Postema, P, Delmar, M, Ellinor, P, Lubitz, S, Gourraud, J, Tanck, M, L. George Jr., A, Macrae, C, Burridge, P, Dina, C, Probst, V, Wilde, A, Schott, J, Redon &, R, Bezzina, C, Julien Barc, Rafik Tadros, Charlotte Glinge, David Y. Chiang, Mariam Jouni, Floriane Simonet, Sean J. Jurgens, Manon Baudic, Michele Nicastro, Franck Potet, Joost A. Offerhaus, Roddy Walsh, Seung Hoan Choi, Arie O. Verkerk, Yuka Mizusawa, Soraya Anys, Damien Minois, Marine Arnaud, Josselin Duchateau, Yanushi D. Wijeyeratne, Alison Muir, Michael Papadakis, Silvia Castelletti, Margherita Torchio, Cristina Gil Ortuño, Javier Lacunza, Daniela F. Giachino, Natascia Cerrato, Raphaël P. Martins, Oscar Campuzano, Sonia Van Dooren, Aurélie Thollet, Florence Kyndt, Andrea Mazzanti, Nicolas Clémenty, Arnaud Bisson, Anniek Corveleyn, Birgit Stallmeyer, Sven Dittmann, Johan Saenen, Antoine Noël, Shohreh Honarbakhsh, Boris Rudic, Halim Marzak, Matthew K. Rowe, Claire Federspiel, Sophie Le Page, Leslie Placide, Antoine Milhem, Hector Barajas-Martinez, Britt-Maria Beckmann, Ingrid P. Krapels, Johannes Steinfurt, Bo Gregers Winkel, Reza Jabbari, Moore B. Shoemaker, Bas J. Boukens, Doris Škorić-Milosavljević, Hennie Bikker, Federico Manevy, Peter Lichtner, Marta Ribasés, Thomas Meitinger, Martina Müller-Nurasyid, KORA-Study Group, Jan H. Veldink, Leonard H. van den Berg, Philip Van Damme, Daniele Cusi, Chiara Lanzani, Sidwell Rigade, Eric Charpentier, Estelle Baron, Stéphanie Bonnaud, Simon Lecointe, Audrey Donnart, Hervé Le Marec, Stéphanie Chatel, Matilde Karakachoff, Stéphane Bézieau, Barry London, Jacob Tfelt-Hansen, Dan Roden, Katja E. Odening, Marina Cerrone, Larry A. Chinitz, Paul G. Volders, Maarten P. van de Berg, Gabriel Laurent, Laurence Faivre, Charles Antzelevitch, Stefan Kääb, Alain Al Arnaout, Jean-Marc Dupuis, Jean-Luc Pasquie, Olivier Billon, Jason D. Roberts, Laurence Jesel, Martin Borggrefe, Pier D. Lambiase, Jacques Mansourati, Bart Loeys, Antoine Leenhardt, Pascale Guicheney, Philippe Maury, Eric Schulze-Bahr, Tomas Robyns, Jeroen Breckpot, Dominique Babuty, Silvia G. Priori, Carlo Napolitano, Nantes Referral Center for inherited cardiac arrhythmia, Carlo de Asmundis, Pedro Brugada, Ramon Brugada, Elena Arbelo, Josep Brugada, Philippe Mabo, Nathalie Behar, Carla Giustetto, Maria Sabater Molina, Juan R. Gimeno, Can Hasdemir, Peter J. Schwartz, Lia Crotti, Pascal P. McKeown, Sanjay Sharma, Elijah R. Behr, Michel Haissaguerre, Frédéric Sacher, Caroline Rooryck, Hanno L. Tan, Carol A. Remme, Pieter G. Postema, Mario Delmar, Patrick T. Ellinor, Steven A. Lubitz, Jean-Baptiste Gourraud, Michael W. Tanck, Alfred L. George Jr., Calum A. MacRae, Paul W. Burridge, Christian Dina, Vincent Probst, Arthur A. Wilde, Jean-Jacques Schott, Richard Redon &, and Connie R. Bezzina
- Abstract
Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings.
- Published
- 2022
12. Transethnic genome-wide association study provides insights in the genetic architecture and heritability of long QT syndrome
- Author
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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, Lahrouchi N, Tadros R, Crotti L, Mizusawa Y, Postema PG, Beekman L, Walsh R, Hasegawa K, Barc J, Ernsting M, Turkowski KL, Mazzanti A, Beckmann BM, Shimamoto K, Diamant UB, Wijeyeratne YD, Kucho Y, Robyns T, Ishikawa T, Arbelo E, Christiansen M, Winbo A, Jabbari R, Lubitz SA, Steinfurt J, Rudic B, Loeys B, Shoemaker MB, Weeke PE, Pfeiffer R, Davies B, Andorin A, Hofman N, Dagradi F, Pedrazzini M, Tester DJ, Bos JM, Sarquella-Brugada G, Campuzano Ó, Platonov PG, Stallmeyer B, Zumhagen S, Nannenberg EA, Veldink JH, van den Berg LH, Al-Chalabi A, Shaw CE, Shaw PJ, Morrison KE, Andersen PM, Müller-Nurasyid M, Cusi D, Barlassina C, Galan P, Lathrop M, Munter M, Werge T, Ribasés M, Aung T, Khor CC, Ozaki M, Lichtner P, Meitinger T, van Tintelen JP, Hoedemaekers Y, Denjoy I, Leenhardt A, Napolitano C, Shimizu W, Schott JJ, Gourraud JB, Makiyama T, Ohno S, Itoh H, Krahn AD, Antzelevitch C, Roden DM, Saenen J, Borggrefe M, Odening KE, Ellinor PT, Tfelt-Hansen J, Skinner JR, van den Berg MP, Olesen MS, Brugada J, Brugada R, Makita N, Breckpot J, Yoshinaga M, Behr ER, Rydberg A, Aiba T, Kääb S, Priori SG, Guicheney P, Tan HL, Newton-Cheh C, Ackerman MJ, Schwartz PJ, Schulze-Bahr E, Probst V, Horie M, Wilde AA, Tanck MWT, Bezzina CR., 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, Lahrouchi N, Tadros R, Crotti L, Mizusawa Y, Postema PG, Beekman L, Walsh R, Hasegawa K, Barc J, Ernsting M, Turkowski KL, Mazzanti A, Beckmann BM, Shimamoto K, Diamant UB, Wijeyeratne YD, Kucho Y, Robyns T, Ishikawa T, Arbelo E, Christiansen M, Winbo A, Jabbari R, Lubitz SA, Steinfurt J, Rudic B, Loeys B, Shoemaker MB, Weeke PE, Pfeiffer R, Davies B, Andorin A, Hofman N, Dagradi F, Pedrazzini M, Tester DJ, Bos JM, Sarquella-Brugada G, Campuzano Ó, Platonov PG, Stallmeyer B, Zumhagen S, Nannenberg EA, Veldink JH, van den Berg LH, Al-Chalabi A, Shaw CE, Shaw PJ, Morrison KE, Andersen PM, Müller-Nurasyid M, Cusi D, Barlassina C, Galan P, Lathrop M, Munter M, Werge T, Ribasés M, Aung T, Khor CC, Ozaki M, Lichtner P, Meitinger T, van Tintelen JP, Hoedemaekers Y, Denjoy I, Leenhardt A, Napolitano C, Shimizu W, Schott JJ, Gourraud JB, Makiyama T, Ohno S, Itoh H, Krahn AD, Antzelevitch C, Roden DM, Saenen J, Borggrefe M, Odening KE, Ellinor PT, Tfelt-Hansen J, Skinner JR, van den Berg MP, Olesen MS, Brugada J, Brugada R, Makita N, Breckpot J, Yoshinaga M, Behr ER, Rydberg A, Aiba T, Kääb S, Priori SG, Guicheney P, Tan HL, Newton-Cheh C, Ackerman MJ, Schwartz PJ, Schulze-Bahr E, Probst V, Horie M, Wilde AA, Tanck MWT, and Bezzina CR.
- 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 (P5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P10-6). 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 (rg=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 c
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- 2020
13. SCN5A mutation type and a genetic risk score associate variably with brugada syndrome phenotype in SCN5A families
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Wijeyeratne, Y, Tanck, M, Mizusawa, Y, Batchvarov, V, Barc, J, Crotti, L, Bos, J, Tester, D, Muir, A, Veltmann, C, Ohno, S, Page, S, Galvin, J, Tadros, R, Muggenthaler, M, Raju, H, Denjoy, I, Schott, J, Gourraud, J, Skoric-Milosavljevic, D, Nannenberg, E, Redon, R, Papadakis, M, Kyndt, F, Dagradi, F, Castelletti, S, Torchio, M, Meitinger, T, Lichtner, P, Ishikawa, T, Wilde, A, Takahashi, K, Sharma, S, Roden, D, Borggrefe, M, Mckeown, P, Shimizu, W, Horie, M, Makita, N, Aiba, T, Ackerman, M, Schwartz, P, Probst, V, Bezzina, C, Behr, E, Wijeyeratne Y. D., Tanck M. W., Mizusawa Y., Batchvarov V., Barc J., Crotti L., Bos J. M., Tester D. J., Muir A., Veltmann C., Ohno S., Page S. P., Galvin J., Tadros R., Muggenthaler M., Raju H., Denjoy I., Schott J. -J., Gourraud J. -B., Skoric-Milosavljevic D., Nannenberg E. A., Redon R., Papadakis M., Kyndt F., Dagradi F., Castelletti S., Torchio M., Meitinger T., Lichtner P., Ishikawa T., Wilde A. A. M., Takahashi K., Sharma S., Roden D. M., Borggrefe M. M., McKeown P. P., Shimizu W., Horie M., Makita N., Aiba T., Ackerman M. J., Schwartz P. J., Probst V., Bezzina C. R., Behr E. R., Wijeyeratne, Y, Tanck, M, Mizusawa, Y, Batchvarov, V, Barc, J, Crotti, L, Bos, J, Tester, D, Muir, A, Veltmann, C, Ohno, S, Page, S, Galvin, J, Tadros, R, Muggenthaler, M, Raju, H, Denjoy, I, Schott, J, Gourraud, J, Skoric-Milosavljevic, D, Nannenberg, E, Redon, R, Papadakis, M, Kyndt, F, Dagradi, F, Castelletti, S, Torchio, M, Meitinger, T, Lichtner, P, Ishikawa, T, Wilde, A, Takahashi, K, Sharma, S, Roden, D, Borggrefe, M, Mckeown, P, Shimizu, W, Horie, M, Makita, N, Aiba, T, Ackerman, M, Schwartz, P, Probst, V, Bezzina, C, Behr, E, Wijeyeratne Y. D., Tanck M. W., Mizusawa Y., Batchvarov V., Barc J., Crotti L., Bos J. M., Tester D. J., Muir A., Veltmann C., Ohno S., Page S. P., Galvin J., Tadros R., Muggenthaler M., Raju H., Denjoy I., Schott J. -J., Gourraud J. -B., Skoric-Milosavljevic D., Nannenberg E. A., Redon R., Papadakis M., Kyndt F., Dagradi F., Castelletti S., Torchio M., Meitinger T., Lichtner P., Ishikawa T., Wilde A. A. M., Takahashi K., Sharma S., Roden D. M., Borggrefe M. M., McKeown P. P., Shimizu W., Horie M., Makita N., Aiba T., Ackerman M. J., Schwartz P. J., Probst V., Bezzina C. R., and Behr E. R.
- Abstract
Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K-SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations. Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles). Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45-11.85]; P=0.0078). Among SCN5A-positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89-6.22]; P=0.0846). In SCN5A-negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84-269.30]; P=0.0146). Among E1784K-SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93-13.62]; P=0.0011). Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.
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- 2020
14. Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls
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Walsh R, Lahrouchi N, Tadros R, Kyndt F, Glinge C, Postema PG, Amin AS, Nannenberg EA, Ware JS, Whiffin N, Mazzarotto F, Škoric-Milosavljevic D, Krijger C, Arbelo E, Babuty D, Barajas-Martinez H, Beckmann BM, Bézieau S, Bos JM, Breckpot J, Campuzano O, Castelletti S, Celen C, Clauss S, Corveleyn A, Crotti L, Dagradi F, de Asmundis C, Denjoy I, Dittmann S, Ellinor PT, Ortuño CG, Giustetto C, Gourraud JB, Hazeki D, Horie M, Ishikawa T, Itoh H, Kaneko Y, Kanters JK, Kimoto H, Kotta MC, Krapels IPC, Kurabayashi M, Lazarte J, Leenhardt A, Loeys BL, Lundin C, Makiyama T, Mansourati J, Martins RP, Mazzanti A, Mörner S, Napolitano C, Ohkubo K, Papadakis M, Rudic B, Molina MS, Sacher F, Sahin H, Sarquella-Brugada G, Sebastiano R, Sharma S, Sheppard MN, Shimamoto K, Shoemaker MB, Stallmeyer B, Steinfurt J, Tanaka Y, Tester DJ, Usuda K, van der Zwaag PA, Van Dooren S, Van Laer L, Winbo A, Winkel BG, Yamagata K, Zumhagen S, Volders PGA, Lubitz SA, Antzelevitch C, Platonov PG, Odening KE, Roden DM, Roberts JD, Skinner JR, Tfelt-Hansen J, van den Berg MP, Olesen MS, Lambiase PD, Borggrefe M, Hayashi K, Rydberg A, Nakajima T, Yoshinaga M, Saenen JB, Kääb S, Brugada P, Robyns T, Giachino DF, Ackerman MJ, Brugada R, Brugada-Terradellas J, Gimeno JR, Hasdemir C, Guicheney P, Priori SG, Schulze-Bahr E, Makita N, Schwartz PJ, Shimizu W, Aiba T, Schott JJ, Redon R, Ohno S, Probst V, Behr ER, Barc J, Bezzina CR, and Nantes Referral Center for inherited cardiac arrhythmia
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,LQTS ,variant interpretation ,cardiovascular diseases ,Brugada ,ACMG/AMP guidelines - 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 × 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 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.
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- 2021
15. GENECHOC study: genetic markers of arrhythmic risk in heart failure
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Anys, S, primary, Rigade, S, additional, Baron, E, additional, Lecointe, S, additional, Guyomarch, B, additional, Klug, D, additional, Babuty, D, additional, Mansourati, J, additional, Bordachar, P, additional, Mabo, P, additional, Thollet, A, additional, Dina, C, additional, Schott, J.J, additional, Barc, J, additional, and Probst, V, additional
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- 2020
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16. Genome-wide association study identifies 18 new susceptibility variants loci associated with Brugada Syndrome
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Barc, J, primary, Trados, R, additional, Glinge, C, additional, Simonet, F, additional, Chiang, D, additional, Jouni, M, additional, Jurgens, S, additional, The Brugada Syndrome Genetic Consortium, B.R.S, additional, Tanck, M, additional, Dina, C, additional, Probst, V, additional, Wilde, A, additional, Redon, R, additional, Schott, J.J, additional, and Bezzina, C, additional
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- 2020
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17. Molecular mechanism of a new cardiac syndrome associated with a regulatory element deletion of chromosome 4q25
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Baudic, M, primary, Murata, H, additional, Le Scouarnec, S, additional, Foucal, A, additional, Lindenbaum, P, additional, Ishikawa, T, additional, Si-Tayeb, K, additional, Gaborit, N, additional, Makita, N, additional, Makiyama, T, additional, Shimizu, W, additional, Vieyres, C, additional, Probst, V, additional, Schott, J.J, additional, and Barc, J, additional
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- 2020
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18. Relevance and diagnostic performance of genes involved in arrhythmogenic cardiomyopathy
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Goudal, A., primary, Karakachoff, M., additional, Lindenbaum, P., additional, Baron, E., additional, Bonnaud, S., additional, Kyndt, F., additional, Bourcereau, E., additional, Thollet, A., additional, Redon, R., additional, Bézieau, S., additional, Schott, J.J., additional, Probst, V., additional, and Barc, J., additional
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- 2020
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19. Genechoc Study Genetic markers of arrhythmic risk in heart failure
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Anys, S., primary, Baron, E., additional, Lecointe, S., additional, Guyomarch, B., additional, Klug, D., additional, Babuty, D., additional, Jesel, L., additional, Dupuis, J.M., additional, Defaye, P., additional, Maury, P., additional, Pasquie, J.L., additional, Le Franc, P., additional, Anselme, F., additional, Boveda, S., additional, Olivier, A., additional, Thollet, A., additional, Dina, C., additional, Schott, J.J., additional, Barc, J., additional, and Probst, V., additional
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- 2020
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20. Identification by Whole Genome Sequencing of a New Gene Causing Hereditary Sinus Node and Atrioventricular Conduction Dysfunction
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Le Guillou, X., primary, Lindenbaum, P., additional, Baron, E., additional, Thollet, A., additional, Kyndt, F., additional, Le Marec, H., additional, Probst, V., additional, Schott, J.J., additional, Gourraud, J.B., additional, and Barc, J., additional
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- 2020
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21. Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome .
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Lahrouchi, N., Tadros, R., Crotti, L., Mizusawa, Y., Postema, P.G., Beekman, L., Walsh, R., Hasegawa, K., Barc, J., Ernsting, M., Turkowski, K.L., Mazzanti, A., Beckmann, B.M., Shimamoto, K., Diamant, U.B., Wijeyeratne, Y.D., Kucho, Y., Robyns, T., Ishikawa, T., Arbelo, E., Christiansen, M., Winbo, A., Jabbari, R., Lubitz, S.A., Steinfurt, J., Rudic, B., Loeys, B., Shoemaker, M.B., Weeke, P.E., Pfeiffer, R., Davies, B., Andorin, A., Hofman, N., Dagradi, F., Pedrazzini, M., Tester, D.J., Bos, J.M, Sarquella-Brugada, G., Campuzano, Ó., Platonov, P.G., Stallmeyer, B., Zumhagen, S., Nannenberg, E.A., Veldink, J.H., Berg, L.H. van den, Al-Chalabi, A., Shaw, C.E., Shaw, P.J., Morrison, K.E., Andersen, P.M., Müller-Nurasyid, M., Cusi, D., Barlassina, C., Galan, P., Lathrop, M., Munter, M., Werge, T., Ribasés, M., Aung, T., Khor, C.C., Ozaki, M., Lichtner, P., Meitinger, T., Tintelen, J.P. van, Hoedemaekers, Y.M., Denjoy, I., Leenhardt, A., Napolitano, C., Shimizu, W., Schott, J.J., Gourraud, J.B., Makiyama, T., Ohno, S., Itoh, H., Krahn, A.D., Antzelevitch, C., Roden, D.M., Saenen, J., Borggrefe, M., Odening, K.E., Ellinor, P.T., Tfelt-Hansen, J., Skinner, J.R., Berg, M.P., Olesen, M.S., Brugada, J., Brugada, R., Makita, N., Breckpot, J., Yoshinaga, M., Behr, E.R., Rydberg, A., Aiba, T., Kääb, S., Priori, S.G., Guicheney, P., Tan, H.L., Newton-Cheh, C., Ackerman, M.J., Schwartz, P.J., Lahrouchi, N., Tadros, R., Crotti, L., Mizusawa, Y., Postema, P.G., Beekman, L., Walsh, R., Hasegawa, K., Barc, J., Ernsting, M., Turkowski, K.L., Mazzanti, A., Beckmann, B.M., Shimamoto, K., Diamant, U.B., Wijeyeratne, Y.D., Kucho, Y., Robyns, T., Ishikawa, T., Arbelo, E., Christiansen, M., Winbo, A., Jabbari, R., Lubitz, S.A., Steinfurt, J., Rudic, B., Loeys, B., Shoemaker, M.B., Weeke, P.E., Pfeiffer, R., Davies, B., Andorin, A., Hofman, N., Dagradi, F., Pedrazzini, M., Tester, D.J., Bos, J.M, Sarquella-Brugada, G., Campuzano, Ó., Platonov, P.G., Stallmeyer, B., Zumhagen, S., Nannenberg, E.A., Veldink, J.H., Berg, L.H. van den, Al-Chalabi, A., Shaw, C.E., Shaw, P.J., Morrison, K.E., Andersen, P.M., Müller-Nurasyid, M., Cusi, D., Barlassina, C., Galan, P., Lathrop, M., Munter, M., Werge, T., Ribasés, M., Aung, T., Khor, C.C., Ozaki, M., Lichtner, P., Meitinger, T., Tintelen, J.P. van, Hoedemaekers, Y.M., Denjoy, I., Leenhardt, A., Napolitano, C., Shimizu, W., Schott, J.J., Gourraud, J.B., Makiyama, T., Ohno, S., Itoh, H., Krahn, A.D., Antzelevitch, C., Roden, D.M., Saenen, J., Borggrefe, M., Odening, K.E., Ellinor, P.T., Tfelt-Hansen, J., Skinner, J.R., Berg, M.P., Olesen, M.S., Brugada, J., Brugada, R., Makita, N., Breckpot, J., Yoshinaga, M., Behr, E.R., Rydberg, A., Aiba, T., Kääb, S., Priori, S.G., Guicheney, P., Tan, H.L., Newton-Cheh, C., Ackerman, M.J., and Schwartz, P.J.
- Abstract
Contains fulltext : 230155.pdf (Publisher’s version ) (Open Access)
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- 2020
22. 98Risk stratification of arrhythmia and death in ARVC
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Gourraud, J.B., primary, Morio, F., additional, Amara, N., additional, Sacher, F., additional, Mabo, P., additional, Babuty, D., additional, Mansourati, J., additional, Pasquie, J.L., additional, Maury, P., additional, Jesel, L., additional, Guyomarch, B., additional, Kyndt, F., additional, Barc, J., additional, Thollet, A., additional, and Probst, V., additional
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- 2017
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23. Risk stratification of arrhythmia and death in ARVC
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Gourraud, J., primary, Morio, F., additional, Amara, N., additional, Sacher, F., additional, Mabo, P., additional, Babuty, D., additional, Mansourati, J., additional, Pasquié, J., additional, Denis, A., additional, Maury, P., additional, Jesel, L., additional, Gilles, L., additional, Solnon, A., additional, Guyomarch, B., additional, Kyndt, F., additional, Barc, J., additional, Thollet, A., additional, and Probst, V., additional
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- 2017
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24. Poster session 1Cell growth, differentiation and stem cells - Heart72Understanding the metabolism of cardiac progenitor cells: a first step towards controlling their proliferation and differentiation?73Expression of pw1/peg3 identifies a new cardiac adult stem cell population involved in post-myocardial infarction remodeling74Long-term stimulation of iPS-derived cardiomyocytes using optogenetic techniques to promote phenotypic changes in E-C coupling75Benefits of electrical stimulation on differentiation and maturation of cardiomyocytes from human induced pluripotent stem cells76Constitutive beta-adrenoceptor-mediated cAMP production controls spontaneous automaticity of human induced pluripotent stem cell-derived cardiomyocytes77Formation and stability of T-tubules in cardiomyocytes78Identification of miRNAs promoting human cardiomyocyte proliferation by regulating Hippo pathway79A direct comparison of foetal to adult epicardial cell activation reveals distinct differences relevant for the post-injury response80Role of neuropilins in zebrafish heart regeneration81Highly efficient immunomagnetic purification of cardiomyocytes derived from human pluripotent stem cells82Cardiac progenitor cells posses a molecular circadian clock and display large 24-hour oscillations in proliferation and stress tolerance83Influence of sirolimus and everolimus on bone marrow-derived mesenchymal stem cell biology84Endoglin is important for epicardial behaviour following cardiac injuryCell death and apoptosis - Heart87Ultrastructural alterations reflecting Ca2+ handling and cell-to-cell coupling disorders precede occurrence of severe arrhythmias in intact animal heart88Urocortin-1 promotes cardioprotection through ERK1/2 and EPAC pathways: role in apoptosis and necrosis89Expression p38 MAPK and Cas-3 in myocardium LV of rats with experimental heart failure at melatonin and enalapril introductionTranscriptional control and RNA species - Heart92Accumulation of beta-amyloid 1-40 in HF patients: the role of lncRNA BACE1-AS93Role of miR-182 in zebrafish and mouse models of Holt-Oram syndrome94Mir-27 distinctly regulates muscle-enriched transcription factors and growth factors in cardiac and skeletal muscle cells95AF risk factors impair PITX2 expression leading to Wnt-microRNA-ion channel remodelingCytokines and cellular inflammation - Heart98Post-infarct survival depends on the interplay of monocytes, neutrophils and interferon gamma in a mouse model of myocardial Infarction99Inflammatory cd11b/c cells play a protective role in compensated cardiac hypertrophy by promoting an orai3-related pro-survival signal100Anti-inflammatory effects of endothelin receptor blockade in the atrial tissue of spontaneously hypertensive rats101Mesenchymal stromal cells reduce NLRP3 inflammasome activity in Coxsackievirus B3-induced myocarditis102Mesenchymal stromal cells modulate monocytes trafficking in Coxsackievirus B3-induced myocarditis103The impact of regulatory T lymphocytes on long-term mortality in patients with chronic heart failure104Temporal dynamics of dendritic cells after ST-elevation myocardial infarction relate with improvement of myocardial functionGrowth factors and neurohormones - Heart107Preconditioning of hypertrophied heart: miR-1 and IGF-1 crosstalk108Modulation of catecholamine secretion from human adrenal chromaffin cells by manipulation of G protein-coupled receptor kinase-2 activity109Evaluation of cyclic adenosin-3,5- monophosphate and neurohormones in patients with chronic heart failureNitric oxide and reactive oxygen species - Heart112Hydrogen sulfide donor inhibits oxidative and nitrosative stress, cardiohemodynamics disturbances and restores cNOS coupling in old rats113Role and mechanisms of action of aldehydes produced by monoamine oxidase A in cardiomyocyte death and heart failure114Exercise training has contrasting effects in myocardial infarction and pressure-overload due to different endothelial nitric oxide synthase regulation115S-Nitroso Human Serum Albumin dose-dependently leads to vasodilation and alters reactive hyperaemia in coronary arteries of an isolated mouse heart model116Modulating endothelial nitric oxide synthase with folic acid attenuates doxorubicin-induced cardiomyopathy119Effects of long-term very high intensity exercise on aortic structure and function in an animal model120Electron paramagnetic resonance spectroscopy quantification of nitrosylated hemoglobin (HbNO) as an index of vascular nitric oxide bioavailability in vivo121Deletion of repressor activator protein 1 impairs acetylcholine-induced relaxation due to production of reactive oxygen speciesExtracellular matrix and fibrosis - Heart124MicroRNA-19b is associated with myocardial collagen cross-linking in patients with severe aortic stenosis. Potential usefulness as a circulating biomarker125A new ex vivo model to study cardiac fibrosis126Heterogeneity of fibrosis and fibroblast differentiation in the left ventricle after myocardial infarction127Effect of carbohydrate metabolism degree compensation to the level of galectin-3 changes in hypertensive patients with chronic heart failure and type 2 diabetes mellitus128Statin paradox in association with calcification of bicuspid aortic valve interstitial cells129Cardiac function remains impaired despite reversible cardiac fibrosis after healed experimental viral myocarditisIon channels, ion exchangers and cellular electrophysiology - Heart132Identifying a novel role for PMCA1 (Atp2b1) in heart rhythm instability133Mutations of the caveolin-3 gene as a predisposing factor for cardiac arrhythmias134The human sinoatrial node action potential: time for a computational model135iPSC-derived cardiomyocytes as a model to dissect ion current alterations of genetic atrial fibrillation136Postextrasystolic potentiation in healthy and diseased hearts: effects of the site of origin and coupling interval of the preceding extrasystole137Absence of Nav1.8-based (late) sodium current in rabbit cardiomyocytes and human iPSC-CMs138hiPSC-derived cardiomyocytes from Brugada Syndrome patients without identified mutations do not exhibit cellular electrophysiological abnormalitiesMicrocirculation141Atherogenic indices, collagen type IV turnover and the development of microvascular complications- study in diabetics with arterial hypertension142Changes in the microvasculature and blood viscosity in women with rheumatoid arthritis, hypercholesterolemia and hypertensionAtherosclerosis145Shear stress regulates endothelial autophagy: consequences on endothelial senescence and atherogenesis146Obstructive sleep apnea causes aortic remodeling in a chronic murine model147Aortic perivascular adipose tissue displays an aged phenotype in early and late atherosclerosis in ApoE-/- mice148A systematic evaluation of the cellular innate immune response during the process of human atherosclerosis149Inhibition of Coagulation factor Xa increases plaque stability and attenuates the onset and progression of atherosclerotic plaque in apolipoprotein e-deficient mice150Regulatory CD4+ T cells from patients with atherosclerosis display pro-inflammatory skewing and enhanced suppression function151Hypoxia-inducible factor (HIF)-1alpha regulates macrophage energy metabolism by mediating miRNAs152Extracellular S100A4 is a key player of smooth muscle cell phenotypic transition: implications in atherosclerosis153Microparticles of healthy origins improve atherosclerosis-associated endothelial progenitor cell dysfunction via microRNA transfer154Arterial remodeling and metabolism impairment in early atherosclerosis155Role of pannexin1 in atherosclerotic plaque formationCalcium fluxes and excitation-contraction coupling158Amphiphysin II induces tubule formation in cardiac cells159Interleukin 1 beta regulation of connexin 43 in cardiac fibroblasts and the effects of adult cardiac myocyte:fibroblast co-culture on myocyte contraction160T-tubular electrical defects contribute to blunted beta-adrenergic response in heart failure161Beat-to-beat variability of intracellular Ca2+ dynamics of Purkinje cells in the infarct border zone of the mouse heart revealed by rapid-scanning confocal microscopy162The efficacy of late sodium current blockers in hypertrophic cardiomyopathy is dependent on genotype: a study on transgenic mouse models with different mutations163Synthesis of cADPR and NAADP by intracellular CD38 in heart: role in inotropic and arrhythmogenic effects of beta-adrenoceptor signalingContractile apparatus166Towards an engineered heart tissue model of HCM using hiPSC expressing the ACTC E99K mutation167Diastolic mechanical load delays structural and functional deterioration of ultrathin adult heart slices in culture168Structural investigation of the cardiac troponin complex by molecular dynamics169Exercise training restores myocardial and oxidative skeletal muscle function from myocardial infarction heart failure ratsOxygen sensing, ischaemia and reperfusion172A novel antibody specific to full-length stromal derived factor-1 alpha reveals that remote conditioning induces its cleavage by endothelial dipeptidyl peptidase 4173Attenuation of myocardial and vascular arginase activity by vagal nerve stimulation via a mechanism involving alpha-7 nicotinic receptor during cardiac ischemia and reperfusion174Novel nanoparticle-mediated medicine for myocardial ischemia-reperfusion injury simultaneously targeting mitochondrial injury and myocardial inflammation175Acetylcholine plays a key role in myocardial ischaemic preconditioning via recruitment of intrinsic cardiac ganglia176The role of nitric oxide and VEGFR-2 signaling in post ischemic revascularization and muscle recovery in aged hypercholesterolemic mice177Efficacy of ischemic preconditioning to protect the human myocardium: the role of clinical conditions and treatmentsCardiomyopathies and fibrosis180Plakophilin-2 haploinsufficiency leads to impaired canonical Wnt signaling in ARVC patient181Improved technique for customized, easier, safer and more reliable transverse aortic arch banding and debanding in mice as a model of pressure overload hypertrophy182Late sodium current inhibitors for the treatment of inducible obstruction and diastolic dysfunction in hypertrophic cardiomyopathy: a study on human myocardium183Angiotensin II receptor antagonist fimasartan has protective role of left ventricular fibrosis and remodeling in the rat ischemic heart184Role of High-Mobility Group Box 1 (HMGB1) redox state on cardiac fibroblasts activities and heart function after myocardial infarction185Atrial remodeling in hypertrophic cardiomyopathy: insights from mouse models carrying different mutations in cTnT186Electrophysiological abnormalities in ventricular cardiomyocytes from a Maine Coon cat with hypertrophic cardiomyopathy: effects of ranolazine187ZBTB17 is a novel cardiomyopathy candidate gene and regulates autophagy in the heart188Inhibition of SRSF4 in cardiomyocytes induces left ventricular hypertrophy189Molecular characterization of a novel cardiomyopathy related desmin frame shift mutation190Autonomic characterisation of electro-mechanical remodeling in an in-vitro leporine model of heart failure191Modulation of Ca2+-regulatory function by three novel mutations in TNNI3 associated with severe infant restrictive cardiomyopathyAging194The aging impact on cardiac mesenchymal like stromal cells (S+P+)195Reversal of premature aging markers after bariatric surgery196Sex-associated differences in vascular remodeling during aging: role of renin-angiotensin system197Role of the receptor for advanced glycation end-products (RAGE) in age dependent left ventricle dysfunctionsGenetics and epigenetics200hsa-miR-21-5p as a key factor in aortic remodeling during aneurysm formation201Co-inheritance of mutations associated with arrhythmogenic and hypertrophic cardiomyopathy in two Italian families202Lamin a/c hot spot codon 190: form various amino acid substitutions to clinical effects203Treatment with aspirin and atorvastatin attenuate cardiac injury induced by rat chest irradiation: Implication of myocardial miR-1, miR-21, connexin-43 and PKCGenomics, proteomics, metabolomics, lipidomics and glycomics206Differential phosphorylation of desmin at serines 27 and 31 drives the accumulation of preamyloid oligomers in heart failure207Potential role of kinase Akt2 in the reduced recovery of type 2 diabetic hearts subjected to ischemia / reperfusion injury208A proteomics comparison of extracellular matrix remodelling in porcine coronary arteries upon stent implantationMetabolism, diabetes mellitus and obesity211Targeting grk2 as therapeutic strategy for cancer associated to diabetes212Effects of salbutamol on large arterial stiffness in patients with metabolic syndrome213Circulating microRNA-1 and microRNA-133a: potential biomarkers of myocardial steatosis in type 2 diabetes mellitus214Anti-inflammatory nutrigenomic effects of hydroxytyrosol in human adipocytes - protective mechanisms of mediterranean diets in obesity-related inflammation215Alterations in the metal content of different cardiac regions within a rat model of diabetic cardiomyopathyTissue engineering218A novel conductive patch for application in cardiac tissue engineering219Establishment of a simplified and improved workflow from neonatal heart dissociation to cardiomyocyte purification and characterization220Effects of flexible substrate on cardiomyocytes cell culture221Mechanical stretching on cardiac adipose progenitors upregulates sarcomere-related genes
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Andre, E, primary, Yaniz-Galende, E, primary, Hamilton, C, primary, Dusting, G J, primary, Hellen, N, primary, Poulet, CE, primary, Diez Cunado, M, primary, Smits, AM, primary, Lowe, V, primary, Eckardt, D, primary, Du Pre, B, primary, Sanz Ruiz, R, primary, Moerkamp, A T, primary, Tribulova, N, primary, Smani, T, primary, Liskova, Y V, primary, Greco, S, primary, Guzzolino, E, primary, Franco, D, primary, Lozano-Velasco, E, primary, Knorr, M, primary, Pavoine, C, primary, Bukowska, A, primary, Van Linthout, S, primary, Miteva, K, primary, Sulzgruber, P, primary, Latet, S C, primary, Portnychenko, A, primary, Cannavo, A, primary, Kamilova, U, primary, Sagach, VF, primary, Santin, Y, primary, Octavia, Y, primary, Haller, PM, primary, Rubies, C, primary, Dei Zotti, F, primary, Wong, KHK, primary, Gonzalez Miqueo, A, primary, Kruithof, BPT, primary, Kadur Nagaraju, C, primary, Shaposhnikova, Y, primary, Songia, P, primary, Lindner, D, primary, Wilson, C, primary, Benzoni, P, primary, Fabbri, A, primary, Campostrini, G, primary, Jorge, E, primary, Casini, S, primary, Mengarelli, I, primary, Nikolov, A, primary, Bublikov, DS, primary, Kheloufi, M, primary, Walker, R E, primary, Van Dijk, RA, primary, Posthuma, JJ, primary, Dumitriu, I E, primary, Karshovska, E, primary, Sakic, A, primary, Alexandru, N, primary, Martin-Lorenzo, M, primary, Molica, F, primary, Taylor, RF, primary, Mcarthur, L, primary, Crocini, C, primary, Matsuyama, T-A, primary, Mazzoni, L, primary, Lin, W K, primary, Owen, TJ, primary, Scigliano, M, primary, Sheehan, A, primary, Bezerra Gurgel, A R, primary, Bromage, DI, primary, Kiss, A, primary, Ikeda, G, primary, Pickard, J M J, primary, Wirth, G, primary, Casos, K, primary, Khudiakov, A, primary, Nistal, JF, primary, Ferrantini, C, primary, Park, S-J, primary, Di Maggio, S, primary, Gentile, F, primary, Dini, L, primary, Buyandelger, B, primary, Larrasa-Alonso, J, primary, Schirmer, I, primary, Chin, SH, primary, Cimiotti, D, primary, Martini, H, primary, Hohensinner, P J, primary, Garabito, M, primary, Zeni, F, primary, Licholai, S, primary, De Bortoli, M, primary, Sivitskaya, L, primary, Viczenczova, C, primary, Rainer, PP, primary, Smith, LE, primary, Suna, G, primary, Gambardella, J, primary, Cozma, A, primary, De Gonzalo Calvo, D, primary, Scoditti, E, primary, Clark, B J, primary, Mansfield, C, primary, Gomez, L, primary, Llucia-Valldeperas, A, primary, De Pauw, A, additional, Porporato, P, additional, Bouzin, C, additional, Draoui, N, additional, Sonveaux, P, additional, Balligand, J-L, additional, Mougenot, N, additional, Formicola, L, additional, Nadaud, S, additional, Dierick, F, additional, Hajjar, RJ, additional, Marazzi, G, additional, Sassoon, D, additional, Hulot, J-S, additional, Zamora, VR, additional, Burton, FL, additional, Macquaide, N, additional, Smith, GL, additional, Hernandez, D, additional, Sivakumaran, P, additional, Millard, R, additional, Wong, RCB, additional, Pebay, A, additional, Shepherd, RK, additional, Lim, SY, additional, Owen, T, additional, Jabbour, RJ, additional, Kloc, M, additional, Kodagoda, T, additional, Denning, C, additional, Harding, SE, additional, Ramos, S, additional, Terracciano, C, additional, Gorelik, J, additional, Wei, K, additional, Bushway, P, additional, Ruiz-Lozano, P, additional, Mercola, M, additional, Moerkamp, AT, additional, Vegh, AMD, additional, Dronkers, E, additional, Lodder, K, additional, Van Herwaarden, T, additional, Goumans, MJ, additional, Pellet-Many, C, additional, Zachary, I, additional, Noack, K, additional, Bosio, A, additional, Feyen, DAM, additional, Demkes, EJ, additional, Dierickx, PJ, additional, Doevendans, PA, additional, Vos, MA, additional, Van Veen, AAB, additional, Van Laake, LW, additional, Fernandez Santos, ME, additional, Suarez Sancho, S, additional, Fuentes Arroyo, L, additional, Plasencia Martin, V, additional, Velasco Sevillano, P, additional, Casado Plasencia, A, additional, Climent, AM, additional, Guillem, M, additional, Atienza Fernandez, F, additional, Fernandez-Aviles, F, additional, Dingenouts, CKE, additional, Kruithof, BPT, additional, Smits, AM, additional, Knezl, V, additional, Szeiffova Bacova, B, additional, Egan Benova, T, additional, Viczenczova, C, additional, Goncalvesova, E, additional, Slezak, J, additional, Calderon-Sanchez, E, additional, Diaz, I, additional, Ordonez, A, additional, Salikova, S P, additional, Zaccagnini, G, additional, Voellenkle, C, additional, Sadeghi, I, additional, Maimone, B, additional, Castelvecchio, S, additional, Gaetano, C, additional, Menicanti, L, additional, Martelli, F, additional, Hatcher, C, additional, D'aurizio, R, additional, Groth, M, additional, Baugmart, M, additional, Mercatanti, A, additional, Russo, F, additional, Mariani, L, additional, Magliaro, C, additional, Pitto, L, additional, Lozano-Velasco, E, additional, Jodar-Garcia, A, additional, Galiano-Torres, J, additional, Lopez-Navarrete, I, additional, Aranega, A, additional, Wagensteen, R, additional, Quesada, A, additional, Franco, D, additional, Finger, S, additional, Karbach, S, additional, Kossmann, S, additional, Muenzel, T, additional, Wenzel, P, additional, Keck, M, additional, Favier, S, additional, Fuand, A, additional, Atassi, F, additional, Barbier, C, additional, Lompre, AM, additional, Hulot, JS, additional, Nikonova, Y, additional, Pluteanu, F, additional, Kockskaemper, J, additional, Chilukoti, RK, additional, Wolke, C, additional, Lendeckel, U, additional, Gardemann, A, additional, Goette, A, additional, Miteva, K, additional, Pappritz, K, additional, Mueller, I, additional, El-Shafeey, M, additional, Ringe, J, additional, Tschoepe, C, additional, Van Linthout, S, additional, Koller, L, additional, Richter, B, additional, Blum, S, additional, Koprak, M, additional, Huelsmann, M, additional, Pacher, R, additional, Goliasch, G, additional, Wojta, J, additional, Niessner, A, additional, Van Herck, P L, additional, Claeys, M J, additional, Haine, S E, additional, Lenders, G D, additional, Miljoen, H P, additional, Segers, V F, additional, Vandendriescche, T R, additional, Hoymans, V Y, additional, Vrints, C J, additional, Lapikova-Bryhinska, T, additional, Gurianova, V, additional, Portnichenko, H, additional, Vasylenko, M, additional, Zapara, Y, additional, Portnichenko, V, additional, Liccardo, D, additional, Lymperopoulos, A, additional, Santangelo, M, additional, Leosco, D, additional, Koch, WJ, additional, Ferrara, N, additional, Rengo, G, additional, Alieva, T, additional, Rasulova, Z, additional, Masharipova, D, additional, Dorofeyeva, N A, additional, Drachuk, KO, additional, Sicard, P, additional, Yucel, Y, additional, Dutaur, M, additional, Vindis, C, additional, Parini, A, additional, Mialet-Perez, J, additional, Van Deel, ED, additional, De Boer, M, additional, De Waard, MC, additional, Duncker, DJ, additional, Nagel, F, additional, Inci, M, additional, Santer, D, additional, Hallstroem, S, additional, Podesser, BK, additional, Kararigas, G, additional, Kietadisorn, R, additional, Swinnen, M, additional, Duimel, H, additional, Verheyen, F, additional, Chrifi, I, additional, Brandt, MM, additional, Cheng, C, additional, Janssens, S, additional, Moens, AL, additional, Batlle, M, additional, Dantas, AP, additional, Sanz, M, additional, Sitges, M, additional, Mont, L, additional, Guasch, E, additional, Lobysheva, I, additional, Beauloye, C, additional, Vanhoutte, PM, additional, Tang, EHC, additional, Beaumont, J, additional, Lopez, B, additional, Ravassa, S, additional, Hermida, N, additional, Valencia, F, additional, Gomez-Doblas, JJ, additional, San Jose, G, additional, De Teresa, E, additional, Diez, J, additional, Van De Merbel, AF, additional, Kruithof-De Julio, M, additional, Claus, P, additional, Dries, E, additional, Angelo Singh, A, additional, Vermeulen, K, additional, Roderick, HL, additional, Sipido, KR, additional, Driesen, RB, additional, Ilchenko, I, additional, Bobronnikova, L, additional, Myasoedova, V, additional, Alamanni, F, additional, Tremoli, E, additional, Poggio, P, additional, Becher, PM, additional, Gotzhein, F, additional, Klingel, K, additional, Blankenberg, S, additional, Westermann, D, additional, Zi, M, additional, Cartwright, E, additional, Campostrini, G, additional, Bonzanni, M, additional, Milanesi, R, additional, Bucchi, A, additional, Baruscotti, M, additional, Difrancesco, D, additional, Barbuti, A, additional, Fantini, M, additional, Wilders, R, additional, Severi, S, additional, Benzoni, P, additional, Dell' Era, P, additional, Serzanti, M, additional, Olesen, MS, additional, Muneretto, C, additional, Bisleri, G, additional, Amoros-Figueras, G, additional, Raga, S, additional, Campos, B, additional, Alonso-Martin, C, additional, Rodriguez-Font, E, additional, Vinolas, X, additional, Cinca, J, additional, Guerra, JM, additional, Mengarelli, I, additional, Schumacher, CA, additional, Veldkamp, MW, additional, Verkerk, AO, additional, Remme, CA, additional, Veerman, C, additional, Guan, K, additional, Stauske, M, additional, Tan, H, additional, Barc, J, additional, Wilde, A, additional, Verkerk, A, additional, Bezzina, C, additional, Tsinlikov, I, additional, Tsinlikova, I, additional, Nicoloff, G, additional, Blazhev, A, additional, Garev, A, additional, Andrienko, AV, additional, Lychev, VG, additional, Vorobova, EN, additional, Anchugina, DA, additional, Vion, AC, additional, Hammoutene, A, additional, Poisson, J, additional, Dupont, N, additional, Souyri, M, additional, Tedgui, A, additional, Codogno, P, additional, Boulanger, CM, additional, Rautou, PE, additional, Torres, M, additional, Montserrat, JM, additional, Almendros, I, additional, Austin, C A, additional, Holt, C M, additional, Rijs, K, additional, Wezel, A, additional, Hamming, JF, additional, Kolodgie, FD, additional, Virmani, R, additional, Schaapherder, AF, additional, Lindeman, JHN, additional, Posma, JJN, additional, Van Oerle, R, additional, Spronk, HMH, additional, Ten Cate, H, additional, Dinkla, S, additional, Kaski, JC, additional, Schober, A, additional, Chaabane, C, additional, Ambartsumian, N, additional, Grigorian, M, additional, Bochaton-Piallat, ML, additional, Dragan, E, additional, Andrei, E, additional, Niculescu, L, additional, Georgescu, A, additional, Gonzalez-Calero, L, additional, Maroto, AS, additional, Martinez, PJ, additional, Heredero, A, additional, Aldamiz-Echevarria, G, additional, Vivanco, F, additional, Alvarez-Llamas, G, additional, Meens, MJ, additional, Pelli, G, additional, Foglia, B, additional, Scemes, E, additional, Kwak, BR, additional, Caldwell, JL, additional, Eisner, DA, additional, Dibb, KM, additional, Trafford, AW, additional, Chilton, L, additional, Smith, G L, additional, Nicklin, S A, additional, Coppini, R, additional, Ferrantini, C, additional, Yan, P, additional, Loew, LM, additional, Poggesi, C, additional, Cerbai, E, additional, Pavone, F S, additional, Sacconi, L, additional, Tanaka, H, additional, Ishibashi-Ueda, H, additional, Takamatsu, T, additional, Gentile, F, additional, Pioner, JM, additional, Santini, L, additional, Sartiani, L, additional, Bargelli, V, additional, Mugelli, A, additional, Maciejewska, M, additional, Bolton, E L, additional, Wang, Y, additional, O'brien, F, additional, Ruas, M, additional, Lei, M, additional, Sitsapesan, R, additional, Galione, A, additional, Terrar, D A, additional, Smith, JG, additional, Garcia, D, additional, Barriales-Villa, R, additional, Monserrat, L, additional, Marston, SB, additional, Watson, S, additional, Tkach, S, additional, Faggian, G, additional, Terracciano, C M, additional, Perbellini, F, additional, Eiros Zamora, J, additional, Papadaki, M, additional, Messer, A, additional, Marston, S, additional, Gould, I, additional, Johnston, A, additional, Dunne, M, additional, Smith, G, additional, Kemi, OJ, additional, Pillai, M, additional, Davidson, SM, additional, Yellon, DM, additional, Tratsiakovich, Y, additional, Jang, J, additional, Gonon, AT, additional, Pernow, J, additional, Matoba, T, additional, Koga, J, additional, Egashira, K, additional, Burke, N, additional, Korpisalo, P, additional, Hakkarainen, H, additional, Laidinen, S, additional, Yla-Herttuala, S, additional, Ferrer-Curriu, G, additional, Perez, M, additional, Permanyer, E, additional, Blasco-Lucas, A, additional, Gracia, JM, additional, Castro, MA, additional, Barquinero, J, additional, Galinanes, M, additional, Kostina, D, additional, Kostareva, A, additional, Malashicheva, A, additional, Merino, D, additional, Ruiz, L, additional, Gomez, J, additional, Juarez, C, additional, Gil, A, additional, Garcia, R, additional, Hurle, MA, additional, Mazzoni, L, additional, Rossi, A, additional, Tesi, C, additional, Belardinelli, L, additional, Olivotto, I, additional, Eun-Ji, EJ, additional, Lim, B-K, additional, Choi, D-J, additional, Milano, G, additional, Bertolotti, M, additional, De Marchis, F, additional, Zollo, F, additional, Sommariva, E, additional, Capogrossi, M C, additional, Pompilio, G, additional, Bianchi, M E, additional, Raucci, A, additional, Scellini, B, additional, Tardiff, J, additional, Diolaiuti, L, additional, Ferrari, P, additional, Mansfield, C, additional, Luther, P, additional, Knoell, R, additional, Villalba, M, additional, Sanchez-Cabo, F, additional, Lopez-Olaneta, MM, additional, Ortiz-Sanchez, P, additional, Garcia-Pavia, P, additional, Lara-Pezzi, E, additional, Klauke, B, additional, Gerdes, D, additional, Schulz, U, additional, Gummert, J, additional, Milting, H, additional, Wake, E, additional, Kocsis-Fodor, G, additional, Brack, KE, additional, Ng, GA, additional, Smolina, N, additional, Majchrzak, M, additional, Moehner, D, additional, Wies, A, additional, Stehle, R, additional, Pfitzer, G, additional, Muegge, A, additional, Jaquet, K, additional, Maggiorani, D, additional, Lefevre, L, additional, Cussac, D, additional, Douin-Echinard, V, additional, Ebenbauer, B, additional, Kaun, C, additional, Prager, M, additional, Rega-Kaun, G, additional, Costa, G, additional, Onetti, Y, additional, Jimenez-Altayo, F, additional, Vila, E, additional, Dantas, A P, additional, Scopece, A, additional, Piacentini, L, additional, Bianchi, ME, additional, Capogrossi, MC, additional, Colombo, G, additional, Blaz, M, additional, Kapelak, B, additional, Sanak, M, additional, Bauce, B, additional, Calore, C, additional, Lorenzon, A, additional, Calore, M, additional, Poloni, G, additional, Mazzotti, E, additional, Rigato, I, additional, Daliento, L, additional, Basso, C, additional, Thiene, G, additional, Melacini, P, additional, Corrado, D, additional, Rampazzo, A, additional, Danilenko, NG, additional, Vaikhanskaya, TG, additional, Davydenko, OG, additional, Kura, B, additional, Yin, CH, additional, Kukreja, R, additional, Tribulova, N, additional, Lee, DI, additional, Sorge, M, additional, Glabe, C, additional, Paolocci, N, additional, Guarnieri, C, additional, Tomaselli, GF, additional, Kass, DA, additional, Van Eyk, JE, additional, Agnetti, G, additional, Cordwell, SJ, additional, White, MY, additional, Wojakowski, W, additional, Lynch, M, additional, Barallobre-Barreiro, J, additional, Yin, X, additional, Mayr, U, additional, White, S, additional, Jahingiri, M, additional, Hill, J, additional, Mayr, M, additional, Sorriento, D, additional, Ciccarelli, M, additional, Fiordelisi, A, additional, Campiglia, P, additional, Trimarco, B, additional, Iaccarino, G, additional, Sitar Taut, AV, additional, Schiau, S, additional, Orasan, O, additional, Halloumi, W, additional, Negrean, V, additional, Zdrenghea, D, additional, Pop, D, additional, Van Der Meer, RW, additional, Rijzewijk, LJ, additional, Smit, JWA, additional, Revuelta-Lopez, E, additional, Nasarre, L, additional, Escola-Gil, JC, additional, Lamb, HJ, additional, Llorente-Cortes, V, additional, Pellegrino, M, additional, Massaro, M, additional, Carluccio, MA, additional, Calabriso, N, additional, Wabitsch, M, additional, Storelli, C, additional, De Caterina, R, additional, Church, S J, additional, Callagy, S, additional, Begley, P, additional, Kureishy, N, additional, Mcharg, S, additional, Bishop, P N, additional, Unwin, R D, additional, Cooper, G J S, additional, Mawad, D, additional, Tonkin, J, additional, Bello, S O, additional, Simonotto, J D, additional, Lyon, A R, additional, Stevens, M M, additional, Harding, S E, additional, Kernbach, M, additional, Czichowski, V, additional, Fuentes, L, additional, Hernandez-Redondo, I, additional, Guillem, MS, additional, Fernandez, ME, additional, Sanz, R, additional, Atienza, F, additional, Soler-Botija, C, additional, Prat-Vidal, C, additional, Galvez-Monton, C, additional, Roura, S, additional, Perea-Gil, I, additional, Bragos, R, additional, and Bayes-Genis, A, additional
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25. Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study
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Behr, E, Savio-Galimberti, E, Barc, J, Holst, A, Petropoulou, E, Prins, B, Jabbari, J, Torchio, M, Berthet, M, Mizusawa, Y, Yang, T, Nannenberg, E, Dagradi, F, Weeke, P, Bastiaenan, R, Ackerman, M, Haunso, S, Leenhardt, A, Kääb, S, Probst, V, Redon, R, Sharma, S, Wilde, A, Tfelt-Hansen, J, Schwartz, P, Roden, D, Bezzina, C, Olesen, M, Darbar, D, Guicheney, P, Crotti, L, Jamshidi, Y, Holst, AG, Behr, E, Savio-Galimberti, E, Barc, J, Holst, A, Petropoulou, E, Prins, B, Jabbari, J, Torchio, M, Berthet, M, Mizusawa, Y, Yang, T, Nannenberg, E, Dagradi, F, Weeke, P, Bastiaenan, R, Ackerman, M, Haunso, S, Leenhardt, A, Kääb, S, Probst, V, Redon, R, Sharma, S, Wilde, A, Tfelt-Hansen, J, Schwartz, P, Roden, D, Bezzina, C, Olesen, M, Darbar, D, Guicheney, P, Crotti, L, Jamshidi, Y, and Holst, AG
- Abstract
Aims: Brugada syndrome (BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. We aimed to identify genetic variation in BrS cases at loci associated with QRS duration. Methods and results: A multi-centre study sequenced seven candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBX3, and TBX5) in 156 Caucasian SCN5A mutation-negative BrS patients (80% male; mean age 48) with symptoms (64%) and/or a family history of sudden death (47%) or BrS (18%). Forty-nine variants were identified: 18 were rare (MAF <1%) and non-synonymous; and 11/18 (61.1%), mostly in SCN10A, were predicted as pathogenic using multiple bioinformatics tools. Allele frequencies were compared with the Exome Sequencing and UK10K Projects. SKAT methods tested rare variation in SCN10A finding no statistically significant difference between cases and controls. Co-segregation analysis was possible for four of seven probands carrying a novel pathogenic variant. Only one pedigree (I671V/G1299A in SCN10A) showed co-segregation. The SCN10A SNP V1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K) OR (95% CI) = 3.02 (2.35-3.87), P = 8.07 × 10-19]. Voltage-clamp experiments for NaV1.8 were performed for SCN10A common variants V1073, A1073, and rare variants of interest: A200V and I671V. V1073, A200V and I671V, demonstrated significant reductions in peak INa compared with ancestral allele A1073 (rs6795970). Conclusion: Rare variants in the screened QRS-associated genes (including SCN10A) are not responsible for a significant proportion of SCN5A mutation negative BrS. The common SNP SCN10A V1073 was strongly associated with BrS and demonstrated loss of NaV1.8 function, as did rare variants in isolated patients.
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- 2015
26. 371 - Risk stratification of arrhythmia and death in ARVC
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Gourraud, J., Morio, F., Amara, N., Sacher, F., Mabo, P., Babuty, D., Mansourati, J., Pasquié, J., Denis, A., Maury, P., Jesel, L., Gilles, L., Solnon, A., Guyomarch, B., Kyndt, F., Barc, J., Thollet, A., and Probst, V.
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- 2017
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27. Genome-wide association analyses identify novel Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility
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Barc, Julien, Tadros, Rafik, Glinge, Charlotte, Chiang, David Y., Jouni, Mariam, Simonet, Floriane, Jurgens, Sean J., Baudic, Manon, Nicastro, Michele, Potet, Franck, Offerhaus, Joost A., Walsh, Roddy, Choi, Seung Hoan, Verkerk, Arie O., Mizusawa, Yuka, Anys, Soraya, Minois, Damien, Arnaud, Marine, Duchateau, Josselin, Wijeyeratne, Yanushi D., Muir, Alison, Papadakis, Michael, Castelletti, Silvia, Torchio, Margherita, Ortuño, Cristina Gil, Lacunza, Javier, Giachino, Daniela F., Cerrato, Natascia, Martins, Raphaël P., Campuzano, Oscar, Van Dooren, Sonia, Thollet, Aurélie, Kyndt, Florence, Mazzanti, Andrea, Clémenty, Nicolas, Bisson, Arnaud, Corveleyn, Anniek, Stallmeyer, Birgit, Dittmann, Sven, Saenen, Johan, Noël, Antoine, Honarbakhsh, Shohreh, Rudic, Boris, Marzak, Halim, Rowe, Matthew K., Federspiel, Claire, Le Page, Sophie, Placide, Leslie, Milhem, Antoine, Barajas-Martinez, Hector, Beckmann, Britt-Maria, Krapels, Ingrid P., Steinfurt, Johannes, Winkel, Bo Gregers, Jabbari, Reza, Shoemaker, Moore B., Boukens, Bas J., Škorić-Milosavljević, Doris, Bikker, Hennie, Manevy, Federico, Lichtner, Peter, Ribasés, Marta, Meitinger, Thomas, Müller-Nurasyid, Martina, Strauch, Konstantin, Peters, Annette, Schulz, Holger, Schwettmann, Lars, Leidl, Reiner, Heier, Margit, Veldink, Jan H., van den Berg, Leonard H., Van Damme, Philip, Cusi, Daniele, Lanzani, Chiara, Rigade, Sidwell, Charpentier, Eric, Baron, Estelle, Bonnaud, Stéphanie, Lecointe, Simon, Donnart, Audrey, Le Marec, Hervé, Chatel, Stéphanie, Karakachoff, Matilde, Bézieau, Stéphane, London, Barry, Tfelt-Hansen, Jacob, Roden, Dan, Odening, Katja E., Cerrone, Marina, Chinitz, Larry A., Volders, Paul G., van de Berg, Maarten P., Laurent, Gabriel, Faivre, Laurence, Antzelevitch, Charles, Kääb, Stefan, Arnaout, Alain Al, Dupuis, Jean-Marc, Pasquie, Jean-Luc, Billon, Olivier, Roberts, Jason D., Jesel, Laurence, Borggrefe, Martin, Lambiase, Pier D., Mansourati, Jacques, Loeys, Bart, Leenhardt, Antoine, Guicheney, Pascale, Maury, Philippe, Schulze-Bahr, Eric, Robyns, Tomas, Breckpot, Jeroen, Babuty, Dominique, Priori, Silvia G., Napolitano, Carlo, Defaye, Pascal, Anselme, Frédéric, Darmon, Jean Philippe, Wiart, François, de Asmundis, Carlo, Brugada, Pedro, Brugada, Ramon, Arbelo, Elena, Brugada, Josep, Mabo, Philippe, Behar, Nathalie, Giustetto, Carla, Molina, Maria Sabater, Gimeno, Juan R., Hasdemir, Can, Schwartz, Peter J., Crotti, Lia, McKeown, Pascal P., Sharma, Sanjay, Behr, Elijah R., Haissaguerre, Michel, Sacher, Frédéric, Rooryck, Caroline, Tan, Hanno L., Remme, Carol A., Postema, Pieter G., Delmar, Mario, Ellinor, Patrick T., Lubitz, Steven A., Gourraud, Jean-Baptiste, Tanck, Michael W., George, Alfred L., MacRae, Calum A., Burridge, Paul W., Dina, Christian, Probst, Vincent, Wilde, Arthur A., Schott, Jean-Jacques, Redon, Richard, Bezzina, Connie R., KORA-Study Group, Nantes Referral Ctr Inherited Card, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Santé - François Bonamy, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Amsterdam UMC - Amsterdam University Medical Center, The MINE study (J.H.V.) has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 772376—EScORIAL). The collaboration project is cofunded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public–private partnerships. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355. The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum München—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. J. Barc is supported by the research program Etoiles montantes des Pays de la Loire REGIOCARD RPH081-U1087-REG-PDL, ANR JCJC LEARN (R21006NN, RPV21014NNA) and by the H2020-MSCA-IF-2014 Program of the European Commission (RISTRAD-661617). R.T. is supported by the Canadian Heart Rhythm Society’s George Mines Award, the European Society of Cardiology research award, and the Philippa and Marvin Carsley Cardiology Chair. D.Y.C. is supported by Fondation Leducq and National Institutes of Health (NIH) NHGRI T32 (no. 1T32HG010464-01). M. Baudic was supported by IRP—VERACITIES—New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES, an I-SITE NExT health and engineering initiative (Ecole Centrale and Nantes University) and by the IRP—GAINES—Genetic Architecture IN cardiovascular disEaSes funded by INSERM and CNRS. R.W. is supported by an Amsterdam Cardiovascular Sciences fellowship. S.C. is supported by the NHLBI BioData Catalyst Fellows Program. C.A.R. is supported by Fondation Leducq, the Dutch Heart Foundation (CVON PREDICT2) and the Innovational Research Incentives Scheme Vidi grant from the Netherlands Organisation for Health Research and Development (ZonMw, 91714371). Y.D.W. is supported by the Robert Lancaster Memorial Fund. M.P. is supported by Cardiac Risk in the Young. S.V.D. is supported by Wetenschappelijk Fonds Willy Gepts VUB-UZ Brussel, project ‘Unravelling the molecular genetic pathways of Brugada Syndrome by cardiomics research’, VUB IRP project ‘IMAGica: an Integrative personalized Medical Approach for Genetic diseases, Inherited Cardia Arrhythmias as a model’ and Innoviris BRIDGE 2017, project ‘IGenCare: Integrated Personalised Medical Genomics Care Solution for Patients with Rare Genetic Diseases’. S.H. is supported by the Barts BRC. B.R. is supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). B.G.W. is supported by the Danish Heart Foundation. M.B.S. is supported by K23HL127704. Project MinE Belgium was supported by a grant from IWT (no. 140935), the ALS Liga België, the National Lottery of Belgium and the KU Leuven Opening the Future Fund. D.C. and C.L. are supported by HYPERGENES (HEALTH-F4-2007). D.R. is supported by R01 HL149826, P50 GM115305. P.J.S. acknowledges the support of Leducq Foundation for Cardiovascular Research grant 18CVD05. P.V.D. is supported by the Netherlands CardioVascular Research Initiative (CVON PREDICT2). C.A. is supported by NIH HL47678 and HL138103, W.W. Smith Charitable Trust and Wistar Morris Fund. M.B. is Supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). P.D.L. is supported by UCL/UCLH Biomedicine NIHR and Barts BRC. B.L. is supported by GOA—Antigone 33933. J.B. is supported by a Senior Clinical Fellowship of the Flemish Science Foundation (FWO). E.B. is supported by the British Heart Foundation including BHF Clinical Research Training Fellowship (FS/11/71/28918: Future diagnostic role and new genetic loci in SADS), Cardiac Risk in the Young and Robert Lancaster Memorial fund sponsored by McColl’s Ltd. Retail Group. H.L.T. is supported by the European Union’s Horizon 2020 research and innovation program under acronym ESCAPE-NET, registered under grant agreement no. 733381, and the Dutch Heart Foundation (CVON RESCUED and PREDICT2 projects). M.D. is supported by NIH-RO1 HL134328. P.T.E. was supported by the Fondation Leducq (14CVD01), the NIH (1RO1HL092577, R01HL128914, K24HL105780), the American Heart Association (18SFRN34110082) and by a research grant from Bayer AG to the Broad Institute. S.A.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. J.-B.G. received a grant from the Fédération Française de Cardiologie (PREVENT project). A.L.G. is supported by the Fondation Leducq. C.A.M.R. is supported by the Leducq Foundation and Burroughs Wellecome Fund. A.A.W. is supported by the Dutch Heart Foundation (CVON PREDICT2 project). J.-J.S. is supported by the Fondation pour la Recherche Médicale (DEQ20140329545). R.R. and P.G. are supported by the National Agency for Research (ANR-GENSUD-14-CE10-0001). C.R.B. is supported by the Dutch Heart Foundation (CVON PREDICT2 project), the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610) and Fondation Leducq (17CVD02)., Barc, J, Tadros, R, Glinge, C, Chiang, D, Jouni, M, Simonet, F, Jurgens, S, Baudic, M, Nicastro, M, Potet, F, Offerhaus, J, Walsh, R, Hoan Choi, S, Verkerk, A, Mizusawa, Y, Anys, S, Minois, D, Arnaud, M, Duchateau, J, Wijeyeratne, Y, Muir, A, Papadakis, M, Castelletti, S, Torchio, M, Gil Ortuño, C, Lacunza, J, Giachino, D, Cerrato, N, Martins, R, Campuzano, O, Van Dooren, S, Thollet, A, Kyndt, F, Mazzanti, A, Clémenty, N, Bisson, A, Corveleyn, A, Stallmeyer, B, Dittmann, S, Saenen, J, Noël, A, Honarbakhsh, S, Rudic, B, Marzak, H, Rowe, M, Federspiel, C, Le Page, S, Placide, L, Milhem, A, Barajas-Martinez, H, Beckmann, B, Krapels, I, Steinfurt, J, Gregers Winkel, B, Jabbari, R, Shoemaker, M, Boukens, B, Škorić-Milosavljević, D, Bikker, H, Manevy, F, Lichtner, P, Ribasés, M, Meitinger, T, Müller-Nurasyid, M, Group, K, Veldink, J, van den Berg, L, Van Damme, P, Cusi, D, Lanzani, C, Rigade, S, Charpentier, E, Baron, E, Bonnaud, S, Lecointe, S, Donnart, A, Le Marec, H, Chatel, S, Karakachoff, M, Bézieau, S, London, B, Tfelt-Hansen, J, Roden, D, Odening, K, Cerrone, M, Chinitz, L, Volders, P, van de Berg, M, Laurent, G, Faivre, L, Antzelevitch, C, Kääb, S, Al Arnaout, A, Dupuis, J, Pasquie, J, Billon, O, Roberts, J, Jesel, L, Borggrefe, M, Lambiase, P, Mansourati, J, Loeys, B, Leenhardt, A, Guicheney, P, Maury, P, Schulze-Bahr, E, Robyns, T, Breckpot, J, Babuty, D, Priori, S, Napolitano, C, Referral Center for inherited cardiac arrhythmia, N, de Asmundis, C, Brugada, P, Brugada, R, Arbelo, E, Brugada, J, Mabo, P, Behar, N, Giustetto, C, Sabater Molina, M, Gimeno, J, Hasdemir, C, Schwartz, P, Crotti, L, Mckeown, P, Sharma, S, Behr, E, Haissaguerre, M, Sacher, F, Rooryck, C, Tan, H, Remme, C, Postema, P, Delmar, M, Ellinor, P, Lubitz, S, Gourraud, J, Tanck, M, L. George Jr., A, Macrae, C, Burridge, P, Dina, C, Probst, V, Wilde, A, Schott, J, Redon &, R, Bezzina, C, Cardiology, Graduate School, Medical Biology, ACS - Amsterdam Cardiovascular Sciences, ACS - Heart failure & arrhythmias, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, APH - Methodology, Epidemiology and Data Science, MUMC+: DA KG Polikliniek (9), RS: Carim - H02 Cardiomyopathy, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H04 Arrhythmogenesis and cardiogenetics, and Cardiovascular Centre (CVC)
- Subjects
EXPRESSION ,[SDV]Life Sciences [q-bio] ,DIAGNOSIS ,GUIDELINES ,ANNOTATION ,Article ,NAV1.5 Voltage-Gated Sodium Channel ,Young Adult ,MANAGEMENT ,Genetics ,GWAS ,Humans ,Genetic Predisposition to Disease ,610 Medicine & health ,SCN5A ,Alleles ,Brugada Syndrome ,Allele ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,HERITABILITY ,Microtubule-Associated Protein ,Brugada Syndrome, GWAS, SNPs ,COMMON VARIANTS ,Mutation ,Disease Susceptibility ,Human medicine ,ENRICHMENT ,Microtubule-Associated Proteins ,SNPs ,Human ,GENERATION ,Genome-Wide Association Study - Abstract
Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na(V)1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na(V)1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings. Genome-wide association analyses identify new susceptibility loci for Brugada syndrome. Functional studies implicate microtubule-related trafficking effects on sodium channel expression as an underlying molecular mechanism., European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program [772376-EScORIAL]; Health~Holland; Top Sector Life Sciences Health; Wellcome Trust [076113, 085475, 090355]; Helmholtz Zentrum Munchen-German Research Center for Environmental Health - German Federal Ministry of Education and Research; State of Bavaria; Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ; research program Etoiles montantes des Pays de la Loire [REGIOCARD RPH081-U1087-REG-PDL]; ANR JCJC LEARN [R21006NN, RPV21014NNA]; H2020-MSCA-IF-2014 Program of the European Commission [RISTRAD-661617]; Canadian Heart Rhythm Society's George Mines Award; European Society of Cardiology research award; Philippa and Marvin Carsley Cardiology Chair; Fondation Leducq; National Institutes of Health (NIH) NHGRI T32 [1T32HG010464-01]; IRP-VERACITIES-New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES an I-SITE NExT health and engineering initiative (Ecole Centrale); IRP-VERACITIES-New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES an I-SITE NExT health and engineering initiative (Nantes University); IRP-GAINES-Genetic Architecture IN cardiovascular disEaSes - INSERM; CNRS; Amsterdam Cardiovascular Sciences fellowship; NHLBI BioData Catalyst Fellows Program; Dutch Heart Foundation [CVON PREDICT2]; Innovational Research Incentives Scheme Vidi grant from the Netherlands Organisation for Health Research and Development (ZonMw) [91714371]; Robert Lancaster Memorial Fund; Cardiac Risk in the Young; Wetenschappelijk Fonds Willy Gepts VUB-UZ Brussel; VUB IRP project `IMAGica: an Integrative personalized Medical Approach for Genetic diseases, Inherited Cardia Arrhythmias as a model' and Innoviris BRIDGE 2017; project `IGenCare: Integrated Personalised Medical Genomics Care Solution for Patients with Rare Genetic Diseases'; Barts BRC; DZHK (German Centre for Cardiovascular Research); BMBF (German Ministry of Education and Research); Danish Heart Foundation; IWT [140935]; ALS Liga Belgie; National Lottery of Belgium; KU Leuven Opening the Future Fund; HYPERGENES [HEALTH-F4-2007]; Leducq Foundation for Cardiovascular Research grant [18CVD05]; Netherlands CardioVascular Research Initiative [CVON PREDICT2]; NIH [HL47678, HL138103, 1RO1HL092577, R01HL128914, K24HL105780]; W.W. Smith Charitable Trust; Wistar Morris Fund; GOA-Antigone [33933]; Senior Clinical Fellowship of the Flemish Science Foundation (FWO); British Heart Foundation; BHF Clinical Research Training Fellowship [FS/11/71/28918]; Cardiac Risk in the Young and Robert Lancaster Memorial fund - McColl's Ltd. Retail Group; European Union's Horizon 2020 research and innovation program under acronym ESCAPE-NET [733381]; Dutch Heart Foundation; Fondation Leducq [14CVD01, 17CVD02]; American Heart Association [18SFRN34110082, 18SFRN34250007]; Bayer AG; NIH grant [1R01HL139731]; Federation Francaise de Cardiologie (PREVENT project); Leducq Foundation; Burroughs Wellecome Fund; Fondation pour la Recherche Medicale [DEQ20140329545]; National Agency for Research [ANR-GENSUD-14-CE10-0001]; Netherlands Organization for Scientific Research (VICI fellowship) [016.150.610]; [K23HL127704]; [R01 HL149826]; [P50 GM115305]; [NIH-RO1 HL134328], We are greatly indebted to the patients included in the study. We thank V. Cotard, C. Goutsmedt, M.-F. Le Cunff and N. Bourgeais for assistance in patient recruitment and L. Beekman for his technical support. We thank the biological resource centre for biobanking (CHU Nantes, Nantes Universite, Centre de ressources biologiques (BB0033-00040), F-44000 Nantes, France) for applying the following guidelines68. We are most grateful to the Genomics and Bioinformatics Core Facility of Nantes (GenoBiRD, Biogenouest, IFB) for its technical support. This research has been conducted using the UK Biobank resource; we are grateful to UK Biobank participants. The MINE study (J.H.V.) has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 772376-EScORIAL). The collaboration project is cofunded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk.Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355. The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum Munchen-German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ. J. Barc is supported by the research program Etoiles montantes des Pays de la Loire REGIOCARD RPH081-U1087-REG-PDL, ANR JCJC LEARN (R21006NN, RPV21014NNA) and by the H2020-MSCA-IF-2014 Program of the European Commission (RISTRAD-661617). R.T. is supported by the Canadian Heart Rhythm Society's George Mines Award, the European Society of Cardiology research award, and the Philippa and Marvin Carsley Cardiology Chair. D.Y.C. is supported by Fondation Leducq and National Institutes of Health (NIH) NHGRI T32 (no. 1T32HG010464-01). M. Baudic was supported by IRP-VERACITIES-New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES, an I-SITE NExT health and engineering initiative (Ecole Centrale and Nantes University) and by the IRP-GAINES-Genetic Architecture IN cardiovascular disEaSes funded by INSERM and CNRS. R.W. is supported by an Amsterdam Cardiovascular Sciences fellowship. S.C. is supported by the NHLBI BioData Catalyst Fellows Program. C.A.R. is supported by Fondation Leducq, the Dutch Heart Foundation (CVON PREDICT2) and the Innovational Research Incentives Scheme Vidi grant from the Netherlands Organisation for Health Research and Development (ZonMw; 91714371). Y.D.W. is supported by the Robert Lancaster Memorial Fund. M.P. is supported by Cardiac Risk in the Young. S.V.D. is supported by Wetenschappelijk Fonds Willy Gepts VUB-UZ Brussel, project `Unravelling the molecular genetic pathways of Brugada Syndrome by cardiomics research', VUB IRP project `IMAGica: an Integrative personalized Medical Approach for Genetic diseases, Inherited Cardia Arrhythmias as a model' and Innoviris BRIDGE 2017, project `IGenCare: Integrated Personalised Medical Genomics Care Solution for Patients with Rare Genetic Diseases'. S.H. is supported by the Barts BRC. B.R.; is supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). B.G.W. is supported by the Danish Heart Foundation. M.B.S. is supported by K23HL127704. Project MinE Belgium was supported by a grant from IWT (no. 140935), the ALS Liga Belgie, the National Lottery of Belgium and the KU Leuven Opening the Future Fund. D.C. and C.L. are supported by HYPERGENES (HEALTH-F4-2007). D.R. is supported by R01 HL149826, P50 GM115305. P.J.S. acknowledges the support of Leducq Foundation for Cardiovascular Research grant 18CVD05. P.V.D. is supported by the Netherlands CardioVascular Research Initiative (CVON PREDICT2). C.A. is supported by NIH HL47678 and HL138103, W.W. Smith Charitable Trust and Wistar Morris Fund. M.B. is Supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). P.D.L. is supported by UCL/UCLH Biomedicine NIHR and Barts BRC. B.L. is supported by GOA-Antigone 33933. J.B. is supported by a Senior Clinical Fellowship of the Flemish Science Foundation (FWO). E.B. is supported by the British Heart Foundation including BHF Clinical Research Training Fellowship (FS/11/71/28918: Future diagnostic role and new genetic loci in SADS), Cardiac Risk in the Young and Robert Lancaster Memorial fund sponsored by McColl's Ltd. Retail Group. H.L.T. is supported by the European Union's Horizon 2020 research and innovation program under acronym ESCAPE-NET, registered under grant agreement no. 733381, and the Dutch Heart Foundation (CVON RESCUED and PREDICT2 projects). M.D. is supported by NIH-RO1 HL134328. P.T.E. was supported by the Fondation Leducq (14CVD01), the NIH (1RO1HL092577, R01HL128914, K24HL105780), the American Heart Association (18SFRN34110082) and by a research grant from Bayer AG to the Broad Institute. S.A.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. J.-B.G. received a grant from the Federation Francaise de Cardiologie (PREVENT project). A.L.G. is supported by the Fondation Leducq. C.A.M.R. is supported by the Leducq Foundation and Burroughs Wellecome Fund. A.A.W. is supported by the Dutch Heart Foundation (CVON PREDICT2 project). J.-J.S. is supported by the Fondation pour la Recherche Medicale (DEQ20140329545). R.R. and P.G. are supported by the National Agency for Research (ANR-GENSUD-14-CE10-0001). C.R.B. is supported by the Dutch Heart Foundation (CVON PREDICT2 project), the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610) and Fondation Leducq (17CVD02).
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- 2022
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28. Cadherin 2-Related Arrhythmogenic Cardiomyopathy: Prevalence and Clinical Features
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Christopher Semsarian, Peter J. Schwartz, J. Peter van Tintelen, Robert M. Hamilton, Cristina Basso, Eric Schulze-Bahr, Jiang Ping Song, Richard N.W. Hauer, Elijah R. Behr, Edgar T. Hoorntje, Bongani M. Mayosi, Michael J. Ackerman, Vincent Probst, Lia Crotti, Hugh Calkins, Daniel P. Judge, Cynthia A. James, Jean-Jacques Schott, Brittney Murray, Alice Ghidoni, Kirti Mittal, Perry M. Elliott, Gianfranco Parati, Davide Gentilini, Maria Christina Kotta, Julien Barc, Petros Syrris, Ghidoni, A, Elliott, P, Syrris, P, Calkins, H, James, C, Judge, D, Murray, B, Barc, J, Probst, V, Schott, J, Song, J, Hauer, R, Hoorntje, E, Van Tintelen, J, Schulze-Bahr, E, Hamilton, R, Mittal, K, Semsarian, C, Behr, E, Ackerman, M, Basso, C, Parati, G, Gentilini, D, Kotta, M, Mayosi, B, Schwartz, P, Crotti, L, and Cardiovascular Centre (CVC)
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0301 basic medicine ,Tachycardia ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Cardiomyopathy ,Disease ,030204 cardiovascular system & hematology ,tachycardia ,sudden cardiac death ,Sudden cardiac death ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Gene Frequency ,Protein Domains ,cadherins ,cardiomyopathy ,mutation ,Internal medicine ,medicine ,Prevalence ,Humans ,Arrhythmogenic Right Ventricular Dysplasia ,Cadherin ,business.industry ,Genetic Variation ,General Medicine ,Original Articles ,Middle Aged ,medicine.disease ,Pedigree ,030104 developmental biology ,medicine.anatomical_structure ,cadherin ,Ventricle ,Mutation (genetic algorithm) ,Cardiology ,Female ,medicine.symptom ,business - Abstract
Background:Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the right and left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants in the nondesmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM.Methods:A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening ofCDH2was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families ofCDH2-positive probands, and clinical evaluation was performed.Results:Genetic screening ofCDH2led to the identification of 7 rare variants: 5, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants inCDH2were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in mostCDH2-positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and sudden cardiac death occurred in 5/9 (56%).Conclusions:In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands withCDH2pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort ofCDH2-ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.
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- 2021
29. SCN5A Mutation Type and a Genetic Risk Score Associate Variably with Brugada Syndrome Phenotype in SCN5A Families
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Peter Lichtner, Thomas Meitinger, Wataru Shimizu, Alison Muir, F. Kyndt, Michael W.T. Tanck, Seiko Ohno, Martina Muggenthaler, Michael J. Ackerman, Vincent Probst, Stephen P. Page, Jean-Jacques Schott, Silvia Castelletti, Hariharan Raju, Jean-Baptiste Gourraud, Joseph Galvin, Taisuke Ishikawa, Eline A. Nannenberg, Dan M. Roden, Doris Škorić-Milosavljević, Kazuhiro Takahashi, Pascal P. McKeown, Federica Dagradi, Lia Crotti, Yanushi D. Wijeyeratne, Julien Barc, Yuka Mizusawa, Peter J. Schwartz, Michael Papadakis, Margherita Torchio, Sanjay Sharma, Velislav N. Batchvarov, Naomasa Makita, Richard Redon, Christian Veltmann, Elijah R. Behr, Takeshi Aiba, Martin Borggrefe, Rafik Tadros, Connie R. Bezzina, J. Martijn Bos, David J. Tester, Isabelle Denjoy, Minoru Horie, Arthur A.M. Wilde, St George's, University of London, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), 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), Centro Cardiologico Monzino [Milano], Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS)-Dpt di Scienze Cliniche e di Comunità [Milano] (DISCCO), Università degli Studi di Milano [Milano] (UNIMI)-Università degli Studi di Milano [Milano] (UNIMI), Mayo Clinic [Rochester], Belfast Health and Social Care Trust, Hannover Medical School [Hannover] (MHH), University of Shiga Prefecture, National Cerebral and Cardiovascular Center (NCCC - OSAKA), Osaka University [Osaka], Leeds Teaching Hospitals NHS Trust, University of Dublin, 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], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Helmholtz-Zentrum München (HZM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Iwate Prefectural University [Takizawa], Vanderbilt University School of Medicine [Nashville], University of Heidelberg, Medical Faculty, Wijeyeratne, Y, Tanck, M, Mizusawa, Y, Batchvarov, V, Barc, J, Crotti, L, Bos, J, Tester, D, Muir, A, Veltmann, C, Ohno, S, Page, S, Galvin, J, Tadros, R, Muggenthaler, M, Raju, H, Denjoy, I, Schott, J, Gourraud, J, Skoric-Milosavljevic, D, Nannenberg, E, Redon, R, Papadakis, M, Kyndt, F, Dagradi, F, Castelletti, S, Torchio, M, Meitinger, T, Lichtner, P, Ishikawa, T, Wilde, A, Takahashi, K, Sharma, S, Roden, D, Borggrefe, M, Mckeown, P, Shimizu, W, Horie, M, Makita, N, Aiba, T, Ackerman, M, Schwartz, P, Probst, V, Bezzina, C, Behr, E, Unité de recherche de l'institut du thorax (ITX-lab), Dpt di Scienze Cliniche e di Comunità [Milano] (DISCCO), Università degli Studi di Milano = University of Milan (UNIMI)-Università degli Studi di Milano = University of Milan (UNIMI)-Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Helmholtz Zentrum München = German Research Center for Environmental Health, HAL-SU, Gestionnaire, Epidemiology and Data Science, APH - Methodology, Graduate School, ACS - Heart failure & arrhythmias, Amsterdam Reproduction & Development (AR&D), Human Genetics, Cardiology, ACS - Pulmonary hypertension & thrombosis, and ACS - Atherosclerosis & ischemic syndromes
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genetics, human ,congenital, hereditary, and neonatal diseases and abnormalities ,Scn5a gene ,phenotype ,BIO/18 - GENETICA ,030204 cardiovascular system & hematology ,risk score ,03 medical and health sciences ,0302 clinical medicine ,Brugada Syndrome ,Genetics, Human ,Penetrance ,Phenotype ,Risk Score ,Medicine ,genetics ,Brugada syndrome ,030212 general & internal medicine ,human ,cardiovascular diseases ,Genetic risk ,penetrance ,Genetics ,Framingham Risk Score ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,business.industry ,fungi ,General Medicine ,Original Articles ,MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE ,medicine.disease ,Human genetics ,3. Good health ,Brugada ECG Pattern ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,cardiovascular system ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Supplemental Digital Content is available in the text., Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K-SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations. Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles). Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45–11.85]; P=0.0078). Among SCN5A-positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89–6.22]; P=0.0846). In SCN5A-negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84–269.30]; P=0.0146). Among E1784K-SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93–13.62]; P=0.0011). Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.
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- 2020
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30. Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls
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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
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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.
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- 2020
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31. Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
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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)
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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.
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- 2020
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32. Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study
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Peter Weeke, Bram P. Prins, Yalda Jamshidi, Stefan Kääb, Margherita Torchio, Evmorfia Petropoulou, Dan M. Roden, Sanjay Sharma, Eline A. Nannenberg, Lia Crotti, Pascale Guicheney, Javad Jabbari, Julien Barc, Tao Yang, Peter J. Schwartz, Anders G. Holst, Eleonora Savio-Galimberti, Morten S. Olesen, Michael J. Ackerman, Connie R. Bezzina, Vincent Probst, Yuka Mizusawa, Dawood Darbar, Elijah R. Behr, Arthur A.M. Wilde, Myriam Berthet, Rachel Bastiaenan, Richard Redon, Antoine Leenhardt, Federica Dagradi, Stig Haunsø, Jacob Tfelt-Hansen, Behr, E, Savio-Galimberti, E, Barc, J, Holst, A, Petropoulou, E, Prins, B, Jabbari, J, Torchio, M, Berthet, M, Mizusawa, Y, Yang, T, Nannenberg, E, Dagradi, F, Weeke, P, Bastiaenan, R, Ackerman, M, Haunso, S, Leenhardt, A, Kääb, S, Probst, V, Redon, R, Sharma, S, Wilde, A, Tfelt-Hansen, J, Schwartz, P, Roden, D, Bezzina, C, Olesen, M, Darbar, D, Guicheney, P, Crotti, L, Jamshidi, Y, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), School of Chemical Engineering [Anshan], University of Science and Technology LiaoNing (USTL), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Service de Cardiologie, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité-Centre de Référence Maladies Cardiaques Héréditaires, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), 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), Unité de recherche de l'institut du thorax (ITX-lab), 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), Cardiology, ACS - Amsterdam Cardiovascular Sciences, and Human Genetics
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Male ,SCN10A ,Candidate gene ,QRS duration ,Heredity ,Physiology ,[SDV]Life Sciences [q-bio] ,DNA Mutational Analysis ,Action Potentials ,Gene Frequency ,Risk Factors ,Databases, Genetic ,Odds Ratio ,humans ,Exome sequencing ,Brugada syndrome ,Genetics ,adult ,Single Nucleotide ,Middle Aged ,Pedigree ,3. Good health ,Europe ,Phenotype ,Female ,Corrigendum ,Cardiology and Cardiovascular Medicine ,Saudi Arabia ,BIO/18 - GENETICA ,Biology ,Transfection ,Polymorphism, Single Nucleotide ,Sudden death ,Cell Line ,NAV1.8 Voltage-Gated Sodium Channel ,Databases ,Genetic ,Physiology (medical) ,Cardiac conduction ,medicine ,Genetic Predisposition to Disease ,Polymorphism ,Allele ,Allele frequency ,Genetic Association Studies ,MED/01 - STATISTICA MEDICA ,Aged ,Genetic heterogeneity ,Computational Biology ,Rare variant ,Rare variants ,Original Articles ,MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE ,medicine.disease ,United States ,Case-Control Studies - Abstract
International audience; AIMS: Brugada syndrome (BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. We aimed to identify genetic variation in BrS cases at loci associated with QRS duration. METHODS AND RESULTS: A multi-centre study sequenced seven candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBX3, and TBX5) in 156 Caucasian SCN5A mutation-negative BrS patients (80% male; mean age 48) with symptoms (64%) and/or a family history of sudden death (47%) or BrS (18%). Forty-nine variants were identified: 18 were rare (MAF \textless1%) and non-synonymous; and 11/18 (61.1%), mostly in SCN10A, were predicted as pathogenic using multiple bioinformatics tools. Allele frequencies were compared with the Exome Sequencing and UK10K Projects. SKAT methods tested rare variation in SCN10A finding no statistically significant difference between cases and controls. Co-segregation analysis was possible for four of seven probands carrying a novel pathogenic variant. Only one pedigree (I671V/G1299A in SCN10A) showed co-segregation. The SCN10A SNP V1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K) OR (95% CI) = 3.02 (2.35-3.87), P = 8.07 × 10-19]. Voltage-clamp experiments for NaV1.8 were performed for SCN10A common variants V1073, A1073, and rare variants of interest: A200V and I671V. V1073, A200V and I671V, demonstrated significant reductions in peak INa compared with ancestral allele A1073 (rs6795970). CONCLUSION: Rare variants in the screened QRS-associated genes (including SCN10A) are not responsible for a significant proportion of SCN5A mutation negative BrS. The common SNP SCN10A V1073 was strongly associated with BrS and demonstrated loss of NaV1.8 function, as did rare variants in isolated patients.
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- 2015
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33. A Rare Noncoding Enhancer Variant in SCN5A Contributes to the High Prevalence of Brugada Syndrome in Thailand.
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Walsh R, Mauleekoonphairoj J, Mengarelli I, Bosada FM, Verkerk AO, van Duijvenboden K, Poovorawan Y, Wongcharoen W, Sutjaporn B, Wandee P, Chimparlee N, Chokesuwattanaskul R, Vongpaisarnsin K, Dangkao P, Wu CI, Tadros R, Amin AS, Lieve KVV, Postema PG, Kooyman M, Beekman L, Sahasatas D, Amnueypol M, Krittayaphong R, Prechawat S, Anannab A, Makarawate P, Ngarmukos T, Phusanti K, Veerakul G, Kingsbury Z, Newington T, Maheswari U, Ross MT, Grace A, Lambiase PD, Behr ER, Schott JJ, Redon R, Barc J, Christoffels VM, Wilde AAM, Nademanee K, Bezzina CR, and Khongphatthanayothin A
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- Humans, Thailand epidemiology, Male, Female, Prevalence, Induced Pluripotent Stem Cells metabolism, Enhancer Elements, Genetic, Adult, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Middle Aged, Genetic Predisposition to Disease, Genetic Variation, Case-Control Studies, NAV1.5 Voltage-Gated Sodium Channel genetics, NAV1.5 Voltage-Gated Sodium Channel metabolism, Brugada Syndrome genetics
- Abstract
Background: Brugada syndrome (BrS) is a cardiac arrhythmia disorder that causes sudden death in young adults. Rare genetic variants in the SCN5A gene encoding the Na
v 1.5 sodium channel and common noncoding variants at this locus are robustly associated with the condition. BrS is particularly prevalent in Southeast Asia but the underlying ancestry-specific factors remain largely unknown., Methods: Genome sequencing of BrS probands and population-matched controls from Thailand was performed to identify rare noncoding variants at the SCN5A-SCN10A locus that were enriched in patients with BrS. A likely causal variant was prioritized by computational methods and introduced into human induced pluripotent stem cell (hiPSC) lines using CRISPR-Cas9. The effect of the variant on SCN5A expression and Nav 1.5 sodium channel current was then assessed in hiPSC-derived cardiomyocytes (hiPSC-CMs)., Results: A rare noncoding variant in an SCN5A intronic enhancer region was highly enriched in patients with BrS (detected in 3.9% of cases with a case-control odds ratio of 45.2). The variant affects a nucleotide conserved across all mammalian species and predicted to disrupt a Mef2 transcription factor binding site. Heterozygous introduction of the enhancer variant in hiPSC-CMs caused significantly reduced SCN5A expression from the variant-containing allele and a 30% reduction in Nav 1.5-mediated sodium current density compared with isogenic controls, confirming its pathogenicity. Patients with the variant had severe phenotypes, with 89% experiencing cardiac arrest., Conclusions: This is the first example of a functionally validated rare noncoding variant at the SCN5A locus and highlights how genome sequencing in understudied populations can identify novel disease mechanisms. The variant partly explains the increased prevalence of BrS in this region and enables the identification of at-risk variant carriers to reduce the burden of sudden cardiac death in Thailand., Competing Interests: None.- Published
- 2025
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34. Novel risk predictor of arrhythmias for patients with potassium channel-related congenital long QT syndrome.
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Krijger Juarez C, Proost VM, Tanck MW, Dittmann S, Bos JM, Crotti L, Barc J, van den Berg MP, Mujkanovic J, Rickert C, Lopes Neves RA, Musu G, Dagradi F, Giovenzana FLF, Clédel A, Thollet A, Giudicessi JR, Tfelt-Hansen J, Probst V, Schwartz PJ, Ackerman MJ, Schulze-Bahr E, Bezzina CR, and Wilde AAM
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Background: Congenital long QT syndrome (LQTS) is characterized by delayed ventricular repolarization, predisposing to potentially lethal ventricular arrhythmias. The variability in disease severity among patients remains largely unexplored, underscoring the limitations of current risk stratification methods., Objective: We aimed to evaluate the potential utility of electrocardiographic markers from the exercise stress test (EST) in identifying patients with high-risk LQTS., Methods: The study, which considered patients with LQTS type 1 and LQTS type 2, comprised a discovery cohort of 695 and a validation cohort of 635 patients., Results: The change in corrected QT (QTc) interval between rest and recovery (between rest and 3-4 minutes into the recovery period, called recovery-rest ΔQTc) was consistently greater in symptomatic patients. Sensitivity analyses performed on EST data obtained on and off β-blockers as well as upon distinguishing between patients with a baseline QTc interval below and those above 470 ms demonstrated consistent findings. The association of recovery-rest ΔQTc with cardiac events remained significant in a subanalysis focusing on future events (ie, occurring after the EST). An optimal recovery-rest ΔQTc cutoff was determined for LQTS type 1 (35 ms) and LQTS type 2 (16 ms) separately and was shown to be significantly associated with cardiac events., Conclusion: Our findings suggest that in patients with LQTS, dynamic QT interval measures obtained during the EST are associated with lifetime arrhythmic events and events after the EST. Such measures can be helpful in identifying a higher-risk subset of patients with LQTS in order to optimize their management. Further research may confirm these findings in larger cohorts and explore the potential benefit of combining genetic and EST data for more precise risk stratification., Competing Interests: Disclosures The authors have no conflicts to disclose., (Copyright © 2024 Heart Rhythm Society. All rights reserved.)
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- 2024
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35. SURFBAT: a surrogate family-based association test building on large imputation reference panels.
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Herzig AF, Rubinacci S, Marenne G, Perdry H, Deleuze JF, Dina C, Barc J, Redon R, Delaneau O, and Génin E
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Genotype-phenotype association tests are typically adjusted for population stratification using principal components that are estimated genome-wide. This lacks resolution when analysing populations with fine structure and/or individuals with fine levels of admixture. This can affect power and precision, and is a particularly relevant consideration when control individuals are recruited using geographic selection criteria. Such is the case in France where we have recently created reference panels of individuals anchored to different geographic regions. To make correct comparisons against case groups, who would likely be gathered from large urban areas, new methods are needed. We present SURFBAT (a SURrogate Family Based Association Test) which performs an approximation of the transmission-disequilibrium test. Our method hinges on the application of genotype imputation algorithms to match similar haplotypes between the case and control groups. This permits us to approximate local ancestry informed posterior probabilities of un-transmitted parental alleles of each case individual. This is achieved by assuming haplotypes from the imputation panel are well matched for ancestry with the case individuals. When the first haplotype of an individual from the imputation panel matches that of a case individual, it is assumed that the second haplotype of the same individual can be used as a locally ancestry matched control haplotype and to approximately impute un-transmitted parental alleles. SURFBAT provides an association test that is inherently robust to fine-scale population stratification and opens up the possibility of efficiently using large imputation reference panels as control groups for association testing. In contrast to other methods for association testing that incorporate local-ancestry inference, SURFBAT does not require a set of ancestry groups to be defined, nor for local ancestry to be explicitly estimated. We demonstrate the interest of our tool on simulated datasets, as well as on a real-data example for a group of case individuals affected by Brugada syndrome., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)
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- 2024
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36. Associations of schizophrenia with arrhythmic disorders and electrocardiogram traits: genetic exploration of population samples.
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Treur JL, Thijssen AB, Smit DJA, Tadros R, Veeneman RR, Denys D, Vermeulen JM, Barc J, Bergstedt J, Pasman JA, Bezzina CR, and Verweij KJH
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Background: An important contributor to the decreased life expectancy of individuals with schizophrenia is sudden cardiac death. Arrhythmic disorders may play an important role herein, but the nature of the relationship between schizophrenia and arrhythmia is unclear., Aims: To assess shared genetic liability and potential causal effects between schizophrenia and arrhythmic disorders and electrocardiogram (ECG) traits., Method: We leveraged summary-level data of large-scale genome-wide association studies of schizophrenia (53 386 cases, 77 258 controls), arrhythmic disorders (atrial fibrillation, 55 114 cases, 482 295 controls; Brugada syndrome, 2820 cases, 10 001 controls) and ECG traits (heart rate (variability), PR interval, QT interval, JT interval and QRS duration, n = 46 952-293 051). We examined shared genetic liability by assessing global and local genetic correlations and conducting functional annotation. Bidirectional causal relations between schizophrenia and arrhythmic disorders and ECG traits were explored using Mendelian randomisation., Results: There was no evidence for global genetic correlation, except between schizophrenia and Brugada syndrome ( r
g = 0.14, 95% CIs = 0.06-0.22, P = 4.0E-04). In contrast, strong positive and negative local correlations between schizophrenia and all cardiac traits were found across the genome. In the most strongly associated regions, genes related to immune and viral response mechanisms were overrepresented. Mendelian randomisation indicated that liability to schizophrenia causally increases Brugada syndrome risk (beta = 0.14, CIs = 0.03-0.25, P = 0.009) and heart rate during activity (beta = 0.25, CIs = 0.05-0.45, P = 0.015)., Conclusions: Despite little evidence for global genetic correlation, specific genomic regions and biological pathways emerged that are important for both schizophrenia and arrhythmia. The putative causal effect of liability to schizophrenia on Brugada syndrome warrants increased cardiac monitoring and early medical intervention in people with schizophrenia.- Published
- 2024
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37. Long-term prognosis of patients with an SCN5A loss-of-function variant and progressive cardiac conduction disorder or Brugada syndrome.
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Tuijnenburg F, Proost VM, Thollet A, Barc J, Groffen AJA, Veerman CC, van der Crabben SN, van der Pas VR, Kyndt F, Jurgens SJ, Tanck MWT, Postema PG, Peter van Tintelen J, Bezzina CR, Probst V, Wilde AAM, Gourraud JB, and Amin AS
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Background: The long-term prognosis of patients with a loss-of-function variant in the cardiac sodium channel gene SCN5A is unknown., Objective: This study aimed to evaluate the long-term arrhythmic risk in patients with an SCN5A loss-of-function variant to identify predictors of arrhythmic events., Methods: Probands and family members with (likely) pathogenic SCN5A loss-of-function variants were retrospectively included. Clinical and electrocardiographic data at baseline and last follow-up were collected. Patients with a history of cardiac arrest, sustained ventricular tachycardia, symptomatic or documented atrial tachy- or bradyarrhythmia, or arrhythmogenic syncope were categorized as symptomatic. Arrhythmic events at follow-up were defined as sudden death, aborted cardiac arrest, documented ventricular fibrillation, and/or sustained ventricular tachycardia., Results: We included 615 patients (349 men, 242 probands, 157 with a spontaneous type 1 Brugada electrocardiogram, and 111 symptomatic at baseline). During a median follow-up of 9.5 (Q1,Q3 5.0-14.3) years, arrhythmic events occurred in 41 patients (6.7%), equating an overall event rate of 0.7%/y: 2.0%/y in symptomatic and 0.3%/y in asymptomatic patients. In the overall study population, symptoms at baseline, male sex, and QRS prolongation were identified as independent predictors of arrhythmic events. In asymptomatic patients, male sex and QRS prolongation were also identified as predictors. Asymptomatic women with QRS interval < 100 ms did not experience arrhythmic events at follow-up., Conclusion: Key predictors of arrhythmic risk in patients with an SCN5A loss-of-function variant, regardless of a Brugada syndrome diagnosis, are symptoms at baseline, male sex, and prolonged QRS interval. Our findings may enable more tailored management strategies in patients with an SCN5A loss-of-function variant based on their individual risk profiles., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)
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- 2024
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38. Genome-Wide Association Study of Accessory Atrioventricular Pathways.
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Aegisdottir HM, Andreasen L, Thorolfsdottir RB, Sveinbjornsson G, Jonsdottir AB, Stefansdottir L, Thorleifsson G, Sigurdsson A, Halldorsson GH, Barc J, Simonet F, Tragante V, Oddsson A, Ferkingstad E, Svendsen JH, Ghouse J, Ahlberg G, Paludan-Müller C, Hadji-Turdeghal K, Bustamante M, Ulfarsson MO, Helgadottir A, Gretarsdottir S, Saevarsdottir S, Jonsdottir I, Erikstrup C, Ullum H, Sørensen E, Brunak S, Jøns C, Zheng C, Bezzina CR, Knowlton KU, Nadauld LD, Sulem P, Ostrowski SR, Pedersen OB, Arnar DO, Gudbjartsson DF, Olesen MS, Bundgaard H, Holm H, and Stefansson K
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- Humans, Male, Female, Adult, Middle Aged, Atrial Fibrillation genetics, Atrial Fibrillation physiopathology, Arrhythmias, Cardiac genetics, Atrioventricular Node physiopathology, Genetic Predisposition to Disease, Denmark epidemiology, Tachycardia, Supraventricular genetics, Tachycardia, Supraventricular physiopathology, Genome-Wide Association Study
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Importance: Understanding of the genetics of accessory atrioventricular pathways (APs) and affiliated arrhythmias is limited., Objective: To investigate the genetics of APs and affiliated arrhythmias., Design, Setting, and Participants: This was a genome-wide association study (GWAS) of APs, defined by International Classification of Diseases (ICD) codes and/or confirmed by electrophysiology (EP) study. Genome-wide significant AP variants were tested for association with AP-affiliated arrhythmias: paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (AF), ventricular tachycardia, and cardiac arrest. AP variants were also tested in data on other heart diseases and measures of cardiac physiology. Individuals with APs and control individuals from Iceland (deCODE Genetics), Denmark (Copenhagen Hospital Biobank, Danish Blood Donor Study, and SupraGen/the Danish General Suburban Population Study [GESUS]), the US (Intermountain Healthcare), and the United Kingdom (UK Biobank) were included. Time of phenotype data collection ranged from January 1983 to December 2022. Data were analyzed from August 2022 to January 2024., Exposures: Sequence variants., Main Outcomes and Measures: Genome-wide significant association of sequence variants with APs., Results: The GWAS included 2310 individuals with APs (median [IQR] age, 43 [28-57] years; 1252 [54.2%] male and 1058 [45.8%] female) and 1 206 977 control individuals (median [IQR] year of birth, 1955 [1945-1970]; 632 888 [52.4%] female and 574 089 [47.6%] male). Of the individuals with APs, 909 had been confirmed in EP study. Three common missense variants were associated with APs, in the genes CCDC141 (p.Arg935Trp: adjusted odds ratio [aOR], 1.37; 95% CI, 1.24-1.52, and p.Ala141Val: aOR, 1.55; 95% CI 1.34-1.80) and SCN10A (p.Ala1073Val: OR, 1.22; 95% CI, 1.15-1.30). The 3 variants associated with PSVT and the SCN10A variant associated with AF, supporting an effect on AP-affiliated arrhythmias. All 3 AP risk alleles were associated with higher heart rate and shorter PR interval, and have reported associations with chronotropic response., Conclusions and Relevance: Associations were found between sequence variants and APs that were also associated with risk of PSVT, and thus likely atrioventricular reentrant tachycardia, but had allele-specific associations with AF and conduction disorders. Genetic variation in the modulation of heart rate, chronotropic response, and atrial or atrioventricular node conduction velocity may play a role in the risk of AP-affiliated arrhythmias. Further research into CCDC141 could provide insights for antiarrhythmic therapeutic targeting in the presence of an AP.
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- 2024
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39. Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci.
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Ishikawa T, Masuda T, Hachiya T, Dina C, Simonet F, Nagata Y, Tanck MWT, Sonehara K, Glinge C, Tadros R, Khongphatthanayothin A, Lu TP, Higuchi C, Nakajima T, Hayashi K, Aizawa Y, Nakano Y, Nogami A, Morita H, Ohno S, Aiba T, Krijger Juárez C, Mauleekoonphairoj J, Poovorawan Y, Gourraud JB, Shimizu W, Probst V, Horie M, Wilde AAM, Redon R, Juang JJ, Nademanee K, Bezzina CR, Barc J, Tanaka T, Okada Y, Schott JJ, and Makita N
- Subjects
- Humans, Japan epidemiology, Male, Europe epidemiology, Female, White People genetics, Middle Aged, Asian People genetics, Case-Control Studies, Adult, Polymorphism, Single Nucleotide genetics, Genome-Wide Association Study, Brugada Syndrome genetics, Genetic Predisposition to Disease genetics
- Abstract
Background and Aims: Brugada syndrome (BrS) is an inherited arrhythmia with a higher disease prevalence and more lethal arrhythmic events in Asians than in Europeans. Genome-wide association studies (GWAS) have revealed its polygenic architecture mainly in European populations. The aim of this study was to identify novel BrS-associated loci and to compare allelic effects across ancestries., Methods: A GWAS was conducted in Japanese participants, involving 940 cases and 1634 controls, followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3760 cases and 11 635 controls). The novel loci were characterized by fine-mapping, gene expression, and splicing quantitative trait associations in the human heart., Results: The Japanese-specific GWAS identified one novel locus near ZSCAN20 (P = 1.0 × 10-8), and the cross-ancestry meta-analysis identified 17 association signals, including six novel loci. The effect directions of the 17 lead variants were consistent (94.1%; P for sign test = 2.7 × 10-4), and their allelic effects were highly correlated across ancestries (Pearson's R = .91; P = 2.9 × 10-7). The genetic risk score derived from the BrS GWAS of European ancestry was significantly associated with the risk of BrS in the Japanese population [odds ratio 2.12 (95% confidence interval 1.94-2.31); P = 1.2 × 10-61], suggesting a shared genetic architecture across ancestries. Functional characterization revealed that a lead variant in CAMK2D promotes alternative splicing, resulting in an isoform switch of calmodulin kinase II-δ, favouring a pro-inflammatory/pro-death pathway., Conclusions: This study demonstrates novel susceptibility loci implicating potentially novel pathogenesis underlying BrS. Despite differences in clinical expressivity and epidemiology, the polygenic architecture of BrS was substantially shared across ancestries., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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40. Generation of a patient-specific induced pluripotent stem cell line carrying the DES p.R406W mutation, an isogenic control and a DES p.R406W knock-in line.
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Geryk M, Canac R, Forest V, Lindenbaum P, Girardeau A, Baudic M, Baron E, Bibonne A, Chariau C, Kyndt F, Redon R, Schott JJ, Gourraud JB, Barc J, and Charpentier F
- Subjects
- Humans, Cell Line, CRISPR-Cas Systems, Gene Knock-In Techniques, Cell Differentiation, Induced Pluripotent Stem Cells metabolism, Desmin metabolism, Desmin genetics, Mutation
- Abstract
Mutations in the DES gene, which encodes the intermediate filament desmin, lead to desminopathy, a rare disease characterized by skeletal muscle weakness and different forms of cardiomyopathies associated with cardiac conduction defects and arrhythmias. We generated human induced pluripotent stem cells (hiPSC) from a patient carrying the DES p.R406W mutation, and employed CRISPR/Cas9 to rectify the mutation in the patient's hiPSC line and introduced the mutation in an hiPSC line from a control individual unrelated to the patient. These hiPSC lines represent useful models for delving into the mechanisms of desminopathy and developing new therapeutic approaches., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2024
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41. TAD boundary deletion causes PITX2-related cardiac electrical and structural defects.
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Baudic M, Murata H, Bosada FM, Melo US, Aizawa T, Lindenbaum P, van der Maarel LE, Guedon A, Baron E, Fremy E, Foucal A, Ishikawa T, Ushinohama H, Jurgens SJ, Choi SH, Kyndt F, Le Scouarnec S, Wakker V, Thollet A, Rajalu A, Takaki T, Ohno S, Shimizu W, Horie M, Kimura T, Ellinor PT, Petit F, Dulac Y, Bru P, Boland A, Deleuze JF, Redon R, Le Marec H, Le Tourneau T, Gourraud JB, Yoshida Y, Makita N, Vieyres C, Makiyama T, Mundlos S, Christoffels VM, Probst V, Schott JJ, and Barc J
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- Humans, Animals, Mice, CCCTC-Binding Factor genetics, CCCTC-Binding Factor metabolism, Chromatin genetics, DNA-Binding Proteins metabolism, Genome, Induced Pluripotent Stem Cells metabolism
- Abstract
While 3D chromatin organization in topologically associating domains (TADs) and loops mediating regulatory element-promoter interactions is crucial for tissue-specific gene regulation, the extent of their involvement in human Mendelian disease is largely unknown. Here, we identify 7 families presenting a new cardiac entity associated with a heterozygous deletion of 2 CTCF binding sites on 4q25, inducing TAD fusion and chromatin conformation remodeling. The CTCF binding sites are located in a gene desert at 1 Mb from the Paired-like homeodomain transcription factor 2 gene (PITX2). By introducing the ortholog of the human deletion in the mouse genome, we recapitulate the patient phenotype and characterize an opposite dysregulation of PITX2 expression in the sinoatrial node (ectopic activation) and ventricle (reduction), respectively. Chromatin conformation assay performed in human induced pluripotent stem cell-derived cardiomyocytes harboring the minimal deletion identified in family#1 reveals a conformation remodeling and fusion of TADs. We conclude that TAD remodeling mediated by deletion of CTCF binding sites causes a new autosomal dominant Mendelian cardiac disorder., (© 2024. The Author(s).)
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- 2024
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42. Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry.
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Crotti L, Spazzolini C, Nyegaard M, Overgaard MT, Kotta MC, Dagradi F, Sala L, Aiba T, Ayers MD, Baban A, Barc J, Beach CM, Behr ER, Bos JM, Cerrone M, Covi P, Cuneo B, Denjoy I, Donner B, Elbert A, Eliasson H, Etheridge SP, Fukuyama M, Girolami F, Hamilton R, Horie M, Iascone M, Jiménez-Jaimez J, Jensen HK, Kannankeril PJ, Kaski JP, Makita N, Muñoz-Esparza C, Odland HH, Ohno S, Papagiannis J, Porretta AP, Prandstetter C, Probst V, Robyns T, Rosenthal E, Rosés-Noguer F, Sekarski N, Singh A, Spentzou G, Stute F, Tfelt-Hansen J, Till J, Tobert KE, Vinocur JM, Webster G, Wilde AAM, Wolf CM, Ackerman MJ, and Schwartz PJ
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- Child, Humans, Death, Sudden, Cardiac etiology, Mutation genetics, Registries, Calmodulin genetics, Long QT Syndrome diagnosis, Long QT Syndrome genetics, Tachycardia, Ventricular diagnosis, Tachycardia, Ventricular genetics
- Abstract
Aims: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms., Methods and Results: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing., Conclusion: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2023
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43. Functional Epicardial Conduction Disturbances Due to a SCN5A Variant Associated With Brugada Syndrome.
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Renard E, Walton RD, Benoist D, Brette F, Bru-Mercier G, Chaigne S, Charron S, Constantin M, Douard M, Dubes V, Guillot B, Hof T, Magat J, Martinez ME, Michel C, Pallares-Lupon N, Pasdois P, Récalde A, Vaillant F, Sacher F, Labrousse L, Rogier J, Kyndt F, Baudic M, Schott JJ, Barc J, Probst V, Sarlandie M, Marionneau C, Ashton JL, Hocini M, Haïssaguerre M, and Bernus O
- Subjects
- Male, Adolescent, Humans, HEK293 Cells, Electrocardiography, Cardiac Conduction System Disease, Death, Sudden, Cardiac, Connexins, Brugada Syndrome
- Abstract
Background: Brugada syndrome is a significant cause of sudden cardiac death (SCD), but the underlying mechanisms remain hypothetical., Objectives: This study aimed to elucidate this knowledge gap through detailed ex vivo human heart studies., Methods: A heart was obtained from a 15-year-old adolescent boy with normal electrocardiogram who experienced SCD. Postmortem genotyping was performed, and clinical examinations were done on first-degree relatives. The right ventricle was optically mapped, followed by high-field magnetic resonance imaging and histology. Connexin-43 and Na
V 1.5 were localized by immunofluorescence, and RNA and protein expression levels were studied. HEK-293 cell surface biotinylation assays were performed to examine NaV 1.5 trafficking., Results: A Brugada-related SCD diagnosis was established for the donor because of a SCN5A Brugada-related variant (p.D356N) inherited from his mother, together with a concomitant NKX2.5 variant of unknown significance. Optical mapping demonstrated a localized epicardial region of impaired conduction near the outflow tract, in the absence of repolarization alterations and microstructural defects, leading to conduction blocks and figure-of-8 patterns. NaV 1.5 and connexin-43 localizations were normal in this region, consistent with the finding that the p.D356N variant does not affect the trafficking, nor the expression of NaV 1.5. Trends of decreased NaV 1.5, connexin-43, and desmoglein-2 protein levels were noted; however, the RT-qPCR results suggested that the NKX2-5 variant was unlikely to be involved., Conclusions: This study demonstrates for the first time that SCD associated with a Brugada-SCN5A variant can be caused by localized functionally, not structurally, impaired conduction., Competing Interests: Funding Support and Author Disclosures This work received financial support from the French Government as part of the “Investments of the Future” program managed by the National Research Agency (ANR-10-IAHU04-LIRYC), the Leducq-Foundation (RHYTHM network, 16CVD02), and the Fondation Coeur et Artères (FC17T2). Dr Barc is supported by the ANR JCJC LEARN (R21006NN, RPV21014NNA). Dr Schott is supported by IRP-, an I-SITE NExT health and engineering initiative (Ecole Centrale & Nantes University) and by the IRP- GAINES funded by INSERM and CNRS. Dr Marionneau is supported by the ANR-16-CE92-0013-01 and the National Institutes of Health (R01-HL148803). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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44. Associations of schizophrenia with arrhythmic disorders and electrocardiogram traits: an in-depth genetic exploration of population samples.
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Treur JL, Thijssen AB, Smit DJ, Tadros R, Veeneman RR, Denys D, Vermeulen JM, Barc J, Bergstedt J, Pasman JA, Bezzina CR, and Verweij KJH
- Abstract
Background: An important contributor to the decreased life expectancy of individuals with schizophrenia is sudden cardiac death. While arrhythmic disorders play an important role in this, the nature of the relation between schizophrenia and arrhythmia is not fully understood., Methods: We leveraged summary-level data of large-scale genome-wide association studies of schizophrenia (53,386 cases 77,258 controls), arrhythmic disorders (atrial fibrillation, 55,114 cases 482,295 controls; Brugada syndrome, 2,820 cases 10,001 controls) and electrocardiogram traits (heart rate (variability), PR interval, QT interval, JT interval, and QRS duration, n=46,952-293,051). First, we examined shared genetic liability by assessing global and local genetic correlations and conducting functional annotation. Next, we explored bidirectional causal relations between schizophrenia and arrhythmic disorders and electrocardiogram traits using Mendelian randomization., Outcomes: There was no evidence for global genetic correlations, except between schizophrenia and Brugada (r
g =0·14, p =4·0E-04). In contrast, strong positive and negative local genetic correlations between schizophrenia and all cardiac traits were found across the genome. In the strongest associated regions, genes related to immune system and viral response mechanisms were overrepresented. Mendelian randomization indicated a causal, increasing effect of liability to schizophrenia on Brugada syndrome (OR=1·15, p =0·009) and heart rate during activity (beta=0·25, p =0·015)., Interpretation: While there was little evidence for global genetic correlations, specific genomic regions and biological pathways important for both schizophrenia and arrhythmic disorders and electrocardiogram traits emerged. The putative causal effect of liability to schizophrenia on Brugada warrants increased cardiac monitoring and potentially early medical intervention in patients with schizophrenia., Funding: European Research Council Starting Grant., Competing Interests: Declaration of interests None of the authors have any conflict of interest to declare- Published
- 2023
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45. Multimodality imaging and transcriptomics to phenotype mitral valve dystrophy in a unique knock-in Filamin-A rat model.
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Delwarde C, Toquet C, Aumond P, Kayvanjoo AH, Foucal A, Le Vely B, Baudic M, Lauzier B, Blandin S, Véziers J, Paul-Gilloteaux P, Lecointe S, Baron E, Massaiu I, Poggio P, Rémy S, Anegon I, Le Marec H, Monassier L, Schott JJ, Mass E, Barc J, Le Tourneau T, Merot J, and Capoulade R
- Subjects
- Adult, Humans, Rats, Animals, Infant, Filamins genetics, Filamins metabolism, Transcriptome, X-Ray Microtomography, Phenotype, Mitral Valve metabolism, Mitral Valve Prolapse pathology
- Abstract
Aims: Degenerative mitral valve dystrophy (MVD) leading to mitral valve prolapse is the most frequent form of MV disease, and there is currently no pharmacological treatment available. The limited understanding of the pathophysiological mechanisms leading to MVD limits our ability to identify therapeutic targets. This study aimed to reveal the main pathophysiological pathways involved in MVD via the multimodality imaging and transcriptomic analysis of the new and unique knock-in (KI) rat model for the FilaminA-P637Q (FlnA-P637Q) mutation associated-MVD., Methods and Results: Wild-type (WT) and KI rats were evaluated morphologically, functionally, and histologically between 3-week-old and 3-to-6-month-old based on Doppler echocardiography, 3D micro-computed tomography (microCT), and standard histology. RNA-sequencing and Assay for Transposase-Accessible Chromatin (ATAC-seq) were performed on 3-week-old WT and KI mitral valves and valvular cells, respectively, to highlight the main signalling pathways associated with MVD. Echocardiographic exploration confirmed MV elongation (2.0 ± 0.1 mm vs. 1.8 ± 0.1, P = 0.001), as well as MV thickening and prolapse in KI animals compared to WT at 3 weeks. 3D MV volume quantified by microCT was significantly increased in KI animals (+58% vs. WT, P = 0.02). Histological analyses revealed a myxomatous remodelling in KI MV characterized by proteoglycans accumulation. A persistent phenotype was observed in adult KI rats. Signalling pathways related to extracellular matrix homeostasis, response to molecular stress, epithelial cell migration, endothelial to mesenchymal transition, chemotaxis and immune cell migration, were identified based on RNA-seq analysis. ATAC-seq analysis points to the critical role of transforming growth factor-β and inflammation in the disease., Conclusion: The KI FlnA-P637Q rat model mimics human myxomatous MVD, offering a unique opportunity to decipher pathophysiological mechanisms related to this disease. Extracellular matrix organization, epithelial cell migration, response to mechanical stress, and a central contribution of immune cells are highlighted as the main signalling pathways leading to myxomatous MVD. Our findings pave the road to decipher underlying molecular mechanisms and the specific role of distinct cell populations in this context., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2023
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46. FACS-assisted CRISPR-Cas9 genome editing of human induced pluripotent stem cells.
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Caillaud A, Lévêque A, Thédrez A, Girardeau A, Canac R, Bray L, Baudic M, Barc J, Gaborit N, Lamirault G, Gardie B, Idriss S, Rimbert A, Le May C, Cariou B, and Si-Tayeb K
- Subjects
- Humans, CRISPR-Cas Systems, Clone Cells, Cell Culture Techniques, Gene Editing methods, Induced Pluripotent Stem Cells
- Abstract
This manuscript proposes an efficient and reproducible protocol for the generation of genetically modified human induced pluripotent stem cells (hiPSCs) by genome editing using CRISPR-Cas9 technology. Here, we describe the experimental strategy for generating knockout (KO) and knockin (KI) clonal populations of hiPSCs using single-cell sorting by flow cytometry. We efficiently achieved up to 15 kb deletions, molecular tag insertions, and single-nucleotide editing in hiPSCs. We emphasize the efficacy of this approach in terms of cell culture time. For complete details on the use and execution of this protocol, please refer to Canac et al. (2022) and Bray et al. (2022)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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47. Burden of rare variants in arrhythmogenic cardiomyopathy with right dominant form-associated genes provides new insights for molecular diagnosis and clinical management.
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Goudal A, Karakachoff M, Lindenbaum P, Baron E, Bonnaud S, Kyndt F, Arnaud M, Minois D, Bourcereau E, Thollet A, Deleuze JF, Genin E, Wiart F, Pasquié JL, Galand V, Sacher F, Dina C, Redon R, Bezieau S, Schott JJ, Probst V, and Barc J
- Subjects
- Desmosomes genetics, Desmosomes metabolism, Genetic Association Studies, Heterozygote, Humans, Plakophilins genetics, Plakophilins metabolism, Arrhythmogenic Right Ventricular Dysplasia diagnosis, Arrhythmogenic Right Ventricular Dysplasia genetics, Arrhythmogenic Right Ventricular Dysplasia metabolism
- Abstract
Arrhythmogenic cardiomyopathy with right dominant form (ACR) is a rare heritable cardiac cardiomyopathy disorder associated with sudden cardiac death. Pathogenic variants (PVs) in desmosomal genes have been causally related to ACR in 40% of cases. Other genes encoding nondesmosomal proteins have been described in ACR, but their contribution in this pathology is still debated. A panel of 71 genes associated with inherited cardiopathies was screened in an ACR population of 172 probands and 856 individuals from the general population. PVs and uncertain significance variants (VUS) have been identified in 36% and 18.6% of patients, respectively. Among the cardiopathy-associated genes, burden tests show a significant enrichment in PV and VUS only for desmosomal genes PKP2 (plakophilin-2), DSP (desmoplakin), DSC2 (desmocollin-2), and DSG2 (desmoglein-2). Importantly, VUS may account for 15% of ACR cases and should then be considered for molecular diagnosis. Among the other genes, no evidence of enrichment was detected, suggesting an extreme caution in the interpretation of these genetic variations without associated functional or segregation data. Genotype-phenotype correlation points to (1) a more severe and earlier onset of the disease in PV and VUS carriers, underlying the importance to carry out presymptomatic diagnosis in relatives and (2) to a more prevalent left ventricular dysfunction in DSP variant carriers., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)
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- 2022
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48. Author Correction: Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.
- Author
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Barc J, Tadros R, Glinge C, Chiang DY, Jouni M, Simonet F, Jurgens SJ, Baudic M, Nicastro M, Potet F, Offerhaus JA, Walsh R, Choi SH, Verkerk AO, Mizusawa Y, Anys S, Minois D, Arnaud M, Duchateau J, Wijeyeratne YD, Muir A, Papadakis M, Castelletti S, Torchio M, Ortuño CG, Lacunza J, Giachino DF, Cerrato N, Martins RP, Campuzano O, Van Dooren S, Thollet A, Kyndt F, Mazzanti A, Clémenty N, Bisson A, Corveleyn A, Stallmeyer B, Dittmann S, Saenen J, Noël A, Honarbakhsh S, Rudic B, Marzak H, Rowe MK, Federspiel C, Le Page S, Placide L, Milhem A, Barajas-Martinez H, Beckmann BM, Krapels IP, Steinfurt J, Winkel BG, Jabbari R, Shoemaker MB, Boukens BJ, Škorić-Milosavljević D, Bikker H, Manevy F, Lichtner P, Ribasés M, Meitinger T, Müller-Nurasyid M, Veldink JH, van den Berg LH, Van Damme P, Cusi D, Lanzani C, Rigade S, Charpentier E, Baron E, Bonnaud S, Lecointe S, Donnart A, Le Marec H, Chatel S, Karakachoff M, Bézieau S, London B, Tfelt-Hansen J, Roden D, Odening KE, Cerrone M, Chinitz LA, Volders PG, van de Berg MP, Laurent G, Faivre L, Antzelevitch C, Kääb S, Arnaout AA, Dupuis JM, Pasquie JL, Billon O, Roberts JD, Jesel L, Borggrefe M, Lambiase PD, Mansourati J, Loeys B, Leenhardt A, Guicheney P, Maury P, Schulze-Bahr E, Robyns T, Breckpot J, Babuty D, Priori SG, Napolitano C, de Asmundis C, Brugada P, Brugada R, Arbelo E, Brugada J, Mabo P, Behar N, Giustetto C, Molina MS, Gimeno JR, Hasdemir C, Schwartz PJ, Crotti L, McKeown PP, Sharma S, Behr ER, Haissaguerre M, Sacher F, Rooryck C, Tan HL, Remme CA, Postema PG, Delmar M, Ellinor PT, Lubitz SA, Gourraud JB, Tanck MW, George AL Jr, MacRae CA, Burridge PW, Dina C, Probst V, Wilde AA, Schott JJ, Redon R, and Bezzina CR
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- 2022
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49. Generation of human induced pluripotent stem cell lines from four unrelated healthy control donors carrying European genetic background.
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Girardeau A, Atticus D, Canac R, Cimarosti B, Caillaud A, Chariau C, Simonet F, Cariou B, Charpentier F, Gourraud JB, Probst V, Belbachir N, Jesel L, Lemarchand P, Barc J, Redon R, Gaborit N, and Lamirault G
- Abstract
Four human induced pluripotent stem cell (hiPSC) lines have been generated from healthy control European donors, and validated. This resource represents a useful tool for stem cell-based research, as references for developmental studies and disease modeling linked to any type of human tissue and organ, in an ethnical-, sex- and age-matched context. They providea reliable in-vitro model for single cell- and tissue-based investigations, and are also a valuable tool for genome editing-based studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
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50. An International Multicenter Cohort Study on β-Blockers for the Treatment of Symptomatic Children With Catecholaminergic Polymorphic Ventricular Tachycardia.
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Peltenburg PJ, Kallas D, Bos JM, Lieve KVV, Franciosi S, Roston TM, Denjoy I, Sorensen KB, Ohno S, Roses-Noguer F, Aiba T, Maltret A, LaPage MJ, Atallah J, Giudicessi JR, Clur SB, Blom NA, Tanck M, Extramiana F, Kato K, Barc J, Borggrefe M, Behr ER, Sarquella-Brugada G, Tfelt-Hansen J, Zorio E, Swan H, Kammeraad JAE, Krahn AD, Davis A, Sacher F, Schwartz PJ, Roberts JD, Skinner JR, van den Berg MP, Kannankeril PJ, Drago F, Robyns T, Haugaa K, Tavacova T, Semsarian C, Till J, Probst V, Brugada R, Shimizu W, Horie M, Leenhardt A, Ackerman MJ, Sanatani S, van der Werf C, and Wilde AAM
- Subjects
- Adolescent, Adrenergic beta-Antagonists pharmacology, Child, Cohort Studies, Female, Humans, Male, Adrenergic beta-Antagonists therapeutic use, Tachycardia, Ventricular drug therapy
- Abstract
Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. β-Blockers decrease this risk, but studies comparing individual β-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of β-blocker in a large cohort of symptomatic children with CPVT., Methods: From 2 international registries of patients with CPVT, RYR2 variant-carrying symptomatic children (defined as syncope or sudden cardiac arrest before β-blocker initiation and age at start of β-blocker therapy <18 years), treated with a β-blocker were included. Cox regression analyses with time-dependent covariates for β-blockers and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope., Results: We included 329 patients (median age at diagnosis, 12 [interquartile range, 7-15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8-12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective β-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a β1-selective β-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial β-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for β1-selective compared with nonselective β-blockers (HR, 2.04 [95% CI, 1.31-3.17]; and HR, 1.99 [95% CI, 1.20-3.30], respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44-4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47-7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08-4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30-5.55])., Conclusions: β1-selective β-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective β-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred β-blocker for treating symptomatic children with CPVT.
- Published
- 2022
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