المؤلفون: Baudic, M., Murata, H., Bosada, F., Souto Melo, U., Aizawa, T., Guedon, A., Lindenbaum, P., Gourraud, J.-B., Makita, N., Mundlos, S., Christoffels, V.M., Makiyama, T., Probst, V., Schott, J.-J., Barc, J.

المصدر: Archives of Cardiovascular Diseases Supplements ; volume 15, issue 1, page 115-116 ; ISSN 1878-6480

مصطلحات موضوعية: Cardiology and Cardiovascular Medicine

الإتاحة: https://doi.org/10.1016Test/j.acvdsp.2022.10.222
https://api.elsevier.com/content/article/PII:S1878648022005031?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S1878648022005031?httpAccept=text/plainTest

المؤلفون: 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.

المساهمون: 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.

مصطلحات موضوعية: ACMG/AMP guideline, Brugada, LQTS, variant interpretation

الوصف: 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.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/32893267; info:eu-repo/semantics/altIdentifier/wos/WOS:000566661000001; volume:23; issue:1; firstpage:47; lastpage:58; numberofpages:12; journal:GENETICS IN MEDICINE; http://hdl.handle.net/2318/1766442Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85090223596; https://www.nature.com/articles/s41436-020-00946-5Test

الإتاحة: https://doi.org/10.1038/s41436-020-00946-5Test
http://hdl.handle.net/2318/1766442Test
https://www.nature.com/articles/s41436-020-00946-5Test

المؤلفون: 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.

المساهمون: 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

مصطلحات موضوعية: cadherin, cardiomyopathy, mutation, sudden cardiac death, tachycardia

الوصف: 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.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/33566628; info:eu-repo/semantics/altIdentifier/wos/WOS:000641550000005; volume:14; issue:2; firstpage:159; lastpage:169; numberofpages:11; journal:CIRCULATION; http://hdl.handle.net/10281/354087Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85104674276

الإتاحة: https://doi.org/10.1161/CIRCGEN.120.003097Test
http://hdl.handle.net/10281/354087Test

المؤلفون: Ghidoni, A, Elliott, PM, Syrris, P, Calkins, H, James, CA, Judge, DP, Murray, B, Barc, J, Probst, V, Schott, J-J, Song, J-P, Hauer, RNW, Hoorntje, ET, van Tintelen, JP, Schulze-Bahr, E, Hamilton, RM, Mittal, K, Semsarian, C, Behr, ER, Ackerman, MJ, Basso, C, Parati, G, Gentilini, D, Kotta, M-C, Mayosi, BM, Schwartz, PJ, Crotti, L

المصدر: Circulation: Genomic and Precision Medicine , 14 (2) , Article e003097. (2021)

مصطلحات موضوعية: Cadherin 2-Related Arrhythmogenic Cardiomyopathy

الوصف: Background - Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibro-fatty replacement of the right and/or 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 non-desmosomal 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 assessed. Results - Genetic screening of CDH2 led to the identification of 7 rare variants: five, 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/or 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.

وصف الملف: text

العلاقة: https://discovery.ucl.ac.uk/id/eprint/10122458/1/003097R2_Merged_PDF.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10122458Test/

الإتاحة: https://discovery.ucl.ac.uk/id/eprint/10122458/1/003097R2_Merged_PDF.pdfTest
https://discovery.ucl.ac.uk/id/eprint/10122458Test/

المؤلفون: Walsh, R, Lahrouchi, N, Tadros, R, Kyndt, F, Glinge, C, Postema, PG, Amin, AS, Nannenberg, EA, Ware, JS, Whiffin, N, Mazzarotto, F, Škorić-Milosavljević, 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, J-B, Hazeki, D, Horie, M, Ishikawa, T, Itoh, H, Kaneko, Y, Kanters, JK, Kimoto, H, Kotta, M-C, 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, J, Gimeno, JR, Hasdemir, C, Guicheney, P, Priori, SG, Schulze-Bahr, E, Makita, N, Schwartz, PJ, Shimizu, W, Aiba, T, Schott, J-J, Redon, R, Ohno, S, Probst, V, Nantes Referral Center for inherited cardiac arrhythmia, Behr, ER, Barc, J, Bezzina, CR

الوصف: 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.

وصف الملف: application/pdf; application/vnd.openxmlformats-officedocument.wordprocessingml.document

العلاقة: https://openaccess.sgul.ac.uk/id/eprint/112371/3/s41436-020-00946-5.pdfTest; https://openaccess.sgul.ac.uk/id/eprint/112371/1/Arrhythmia_variant_interpretation_manuscript_GiM_FINAL_Figs_Tables.docxTest; Walsh, R; Lahrouchi, N; Tadros, R; Kyndt, F; Glinge, C; Postema, PG; Amin, AS; Nannenberg, EA; Ware, JS; Whiffin, N; et al. Walsh, R; Lahrouchi, N; Tadros, R; Kyndt, F; Glinge, C; Postema, PG; Amin, AS; Nannenberg, EA; Ware, JS; Whiffin, N; Mazzarotto, F; Škorić-Milosavljević, 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, J-B; Hazeki, D; Horie, M; Ishikawa, T; Itoh, H; Kaneko, Y; Kanters, JK; Kimoto, H; Kotta, M-C; 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, J; Gimeno, JR; Hasdemir, C; Guicheney, P; Priori, SG; Schulze-Bahr, E; Makita, N; Schwartz, PJ; Shimizu, W; Aiba, T; Schott, J-J; Redon, R; Ohno, S; Probst, V; Nantes Referral Center for inherited cardiac arrhythmia; Behr, ER; Barc, J; Bezzina, CR (2021) Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. Genet Med, 23 (1). pp. 47-58. ISSN 1530-0366 https://doi.org/10.1038/s41436-020-00946-5Test SGUL Authors: Behr, Elijah Raphael Papadakis, Michael Sharma, Sanjay Sheppard, Mary Noelle

الإتاحة: https://doi.org/10.1038/s41436-020-00946-5Test
https://openaccess.sgul.ac.uk/id/eprint/112371Test/
https://openaccess.sgul.ac.uk/id/eprint/112371/3/s41436-020-00946-5.pdfTest
https://openaccess.sgul.ac.uk/id/eprint/112371/1/Arrhythmia_variant_interpretation_manuscript_GiM_FINAL_Figs_Tables.docxTest

المؤلفون: Delwarde, C, Aumond, P, Toquet, C, Lauzier, B, Veziers, J, Blandin, S, Kayvanjoo, A, Mass, E, Remy, S, Anegon, I, Schott, J J, Le Tourneau, T, Merot, J, Capoulade, R

المصدر: European Heart Journal ; volume 42, issue Supplement_1 ; ISSN 0195-668X 1522-9645

مصطلحات موضوعية: Cardiology and Cardiovascular Medicine

الوصف: Introduction Mitral Valve Prolapse (MVP) affects 3% of the population and is characterized by a heterogeneous mitral leaflet remodeling. The pathophysiological mechanisms involved in MVP development are not fully understood, the only therapeutic option remains the surgical valve replacement. We previously identified FLNA as the first gene causing MVP and recently generated a unique knock-in rat model for the FLNA-P637Q mutation that now paves the road to study the molecular mechanisms involved in MVP development. Purpose The aim of our study was to characterize the morphological, functional and molecular expression of the valvular disease in our unique KI rat model. Methods 5 wild-type (WT) and 10 KI rats were evaluated at 3, 6 and 13 weeks. Comprehensive 2D echocardiography was performed to determine valve function and morphology. 3D quantitative analysis of the mitral valve (MV) remodelling was done using micro computed tomography (microCT). MV tissue composition was analysed based on histological and immunohistochemistry. Transcriptomic comparison was performed using RNA-sequencing approach. Results Based on the qualitative echocardiographic assessment of the valve, a high genotype-phenotype concordance was established for WT and KI animals (100%, 93% and 100% matching for each time points). The anterior leaflet was longer in KI comparatively to WT rats (+12 to +14% increase at all time points (p<0.01)). Increased lengths corroborated the increased leaflets volume assessed by microCT analysis (+20 to +58% in KI compared to WT all time points (p<0.05)). Histological and immunohistological analyses (leaflet's thickening, hypercellularity, proteoglycans accumulation without calcification) pointed out towards a myxomatous valve disease. The differential gene expression profile established by RNAseq analysis revealed that inflammation, epithelial cell migration or mechanical transduction pathways were specifically activated in KI valves. Genes such as Itgb2 (+1.30x), Ccl12 (+2.44x), Ccl2 ...

الإتاحة: https://doi.org/10.1093/eurheartj/ehab724.1559Test
https://academic.oup.com/eurheartj/article-pdf/42/Supplement_1/ehab724.1559/41054222/ehab724.1559.pdfTest

المؤلفون: 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.

المساهمون: 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

مصطلحات موضوعية: Brugada syndrome, genetics, human, penetrance, phenotype, risk score, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, BIO/18 - GENETICA

الوصف: 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.

وصف الملف: STAMPA

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/33164571; info:eu-repo/semantics/altIdentifier/wos/WOS:000598974000004; volume:13; issue:6; firstpage:599; lastpage:608; numberofpages:10; journal:CIRCULATION; http://hdl.handle.net/10281/298048Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85097964476

الإتاحة: https://doi.org/10.1161/CIRCGEN.120.002911Test
http://hdl.handle.net/10281/298048Test

المؤلفون: Perrot N., Valerio V., Moschetta D., Boekholdt S. M., Dina C., Chen H. Y., Abner E., Martinsson A., Manikpurage H. D., Rigade S., Capoulade R., Mass E., Clavel M. -A., Le Tourneau T., Messika-Zeitoun D., Wareham N. J., Engert J. C., Polvani G., Pibarot P., Esko T., Smith J. G., Mathieu P., Thanassoulis G., Schott J. -J., Bosse Y., Camera M., Theriault S., Poggio P., Arsenault B. J.

المساهمون: N. Perrot, V. Valerio, D. Moschetta, S.M. Boekholdt, C. Dina, H.Y. Chen, E. Abner, A. Martinsson, H.D. Manikpurage, S. Rigade, R. Capoulade, E. Ma, M.-. Clavel, T. Le Tourneau, D. Messika-Zeitoun, N.J. Wareham, J.C. Engert, G. Polvani, P. Pibarot, T. Esko, J.G. Smith, P. Mathieu, G. Thanassouli, J.-. Schott, Y. Bosse, M. Camera, S. Theriault, P. Poggio, B.J. Arsenault

مصطلحات موضوعية: aortic valve interstitial cell, apolipoprotein B, calcific aortic valve stenosi, LDL cholesterol, lipoprotein(a), proprotein convertase subtilisin/kexin type 9, Settore BIO/14 - Farmacologia

الوصف: The authors investigated whether PCSK9 inhibition could represent a therapeutic strategy in calcific aortic valve stenosis (CAVS). A meta-analysis of 10 studies was performed to determine the impact of the PCSK9 R46L variant on CAVS, and the authors found that CAVS was less prevalent in carriers of this variant (odds ratio: 0.80 [95% confidence interval: 0.70 to 0.91]; p = 0.0011) compared with noncarriers. PCSK9 expression was higher in the aortic valves of patients CAVS compared with control patients. In human valve interstitials cells submitted to a pro-osteogenic medium, PCSK9 levels increased and a PCSK9 neutralizing antibody significantly reduced calcium accumulation.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/32760854; info:eu-repo/semantics/altIdentifier/wos/WOS:000601148000001; volume:5; issue:7; firstpage:649; lastpage:661; numberofpages:13; journal:JACC. BASIC TO TRANSLATIONAL SCIENCE; http://hdl.handle.net/2434/758040Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85087405073

الإتاحة: https://doi.org/10.1016Test/j.jacbts.2020.05.004
http://hdl.handle.net/2434/758040Test

المؤلفون: Walsh, R, Lahrouchi, N, Tadros, R, Kyndt, F, Glinge, C, Postema, PG, Amin, AS, Nannenberg, EA, Ware, JS, Whiffin, N, Mazzarotto, F, Skoric-Milosavljevic, D, Krijger, C, Arbelo, E, Babuty, D, Barajas-Martinez, H, Beckmann, BM, Bezieau, 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, Ortuno, CG, Giustetto, C, Gourraud, J-B, Hazeki, D, Horie, M, Ishikawa, T, Itoh, H, Kaneko, Y, Kanters, JK, Kimoto, H, Kotta, M-C, Krapels, IPC, Kurabayashi, M, Lazarte, J, Leenhardt, A, Loeys, BL, Lundin, C, Makiyama, T, Mansourati, J, Martins, RP, Mazzanti, A, Morner, 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, Kaeaeb, S, Brugada, P, Robyns, T, Giachino, DF, Ackerman, MJ, Brugada, R, Brugada, J, Gimeno, JR, Hasdemir, C, Guicheney, P, Priori, SG, Schulze-Bahr, E, Makita, N, Schwartz, PJ, Shimizu, W, Aiba, T, Schott, J-J, Redon, R, Ohno, S, Probst, V, Behr, ER, Barc, J, Bezzina, CR

المصدر: Genetics in Medicine (2020) (In press).

مصطلحات موضوعية: variant interpretation, LQTS, Brugada, ACMG/AMP guidelines

الوصف: 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.

وصف الملف: text

العلاقة: https://discovery.ucl.ac.uk/id/eprint/10112002/1/Lambiase_Enhancing%20rare%20variant%20interpretation%20in%20inherited%20arrhythmias%20through%20quantitative%20analysis%20of%20consortium%20disease%20cohorts%20and%20population%20controls_AOP.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10112002Test/

الإتاحة: https://discovery.ucl.ac.uk/id/eprint/10112002/1/Lambiase_Enhancing%20rare%20variant%20interpretation%20in%20inherited%20arrhythmias%20through%20quantitative%20analysis%20of%20consortium%20disease%20cohorts%20and%20population%20controls_AOP.pdfTest
https://discovery.ucl.ac.uk/id/eprint/10112002Test/

المؤلفون: Wijeyeratne, YD, Tanck, MW, Mizusawa, Y, Batchvarov, V, Barc, J, Crotti, L, Bos, JM, Tester, DJ, Muir, A, Veltmann, C, Ohno, S, Page, SP, Galvin, J, Tadros, R, Muggenthaler, M, Raju, H, Denjoy, I, Schott, J-J, Gourraud, J-B, Skoric-Milosavljevic, D, Nannenberg, EA, Redon, R, Papadakis, M, Kyndt, F, Dagradi, F, Castelletti, S, Torchio, M, Meitinger, T, Lichtner, P, Ishikawa, T, Wilde, AAM, Takahashi, K, Sharma, S, Roden, DM, Borggrefe, MM, McKeown, PP, Shimizu, W, Horie, M, Makita, N, Aiba, T, Ackerman, MJ, Schwartz, PJ, Probst, V, Bezzina, CR, Behr, ER

الوصف: 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 (SNP) 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 SNP risk alleles). Results - In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio (OR) of 4.15 for BrS phenotype (95%CI:1.45-11.85, p=0.0078). Amongst SCN5A-positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio (OR) of 2.35 (95%CI:0.89-6.22, p=0.0846). In SCN5A-negative relatives (n=54), BrS-GRS ≥4 alleles yielded and OR 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 OR=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.

وصف الملف: application/pdf

العلاقة: https://openaccess.sgul.ac.uk/id/eprint/112608/1/CIRCGEN.120.002911.pdfTest; Wijeyeratne, YD; Tanck, MW; Mizusawa, Y; Batchvarov, V; Barc, J; Crotti, L; Bos, JM; Tester, DJ; Muir, A; Veltmann, C; et al. Wijeyeratne, YD; Tanck, MW; Mizusawa, Y; Batchvarov, V; Barc, J; Crotti, L; Bos, JM; Tester, DJ; Muir, A; Veltmann, C; Ohno, S; Page, SP; Galvin, J; Tadros, R; Muggenthaler, M; Raju, H; Denjoy, I; Schott, J-J; Gourraud, J-B; Skoric-Milosavljevic, D; Nannenberg, EA; Redon, R; Papadakis, M; Kyndt, F; Dagradi, F; Castelletti, S; Torchio, M; Meitinger, T; Lichtner, P; Ishikawa, T; Wilde, AAM; Takahashi, K; Sharma, S; Roden, DM; Borggrefe, MM; McKeown, PP; Shimizu, W; Horie, M; Makita, N; Aiba, T; Ackerman, MJ; Schwartz, PJ; Probst, V; Bezzina, CR; Behr, ER (2020) SCN5A Mutation Type and a Genetic Risk Score Associate Variably with Brugada Syndrome Phenotype in SCN5A Families. Circ Genom Precis Med, 13 (6). ISSN 2574-8300 https://doi.org/10.1161/CIRCGEN.120.002911Test SGUL Authors: Behr, Elijah Raphael Sharma, Sanjay

الإتاحة: https://doi.org/10.1161/CIRCGEN.120.002911Test
https://openaccess.sgul.ac.uk/id/eprint/112608Test/
https://openaccess.sgul.ac.uk/id/eprint/112608/1/CIRCGEN.120.002911.pdfTest