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1. In vivo KCNQ1-suppression-replacement gene therapy in transgenic LQT1 rabbits restores a physiological QT interval at baseline and under catecholamine infusion

Author

Giammarino, L, primary, Bains, S, additional, Louradour, J, additional, Nimani, S, additional, Alerni, N, additional, Tester, D, additional, Christoforou, N, additional, Horvath, A, additional, Beslac, O, additional, Koren, G, additional, Brunner, M, additional, Casoni, D, additional, Haeberlin, A, additional, Ackerman, M J, additional, and Odening, K E, additional

Published
2024
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2. In vivo KCNH2-suppression-replacement gene therapy attenuates the pathogenic phenotype in transgenic rabbits with short QT syndrome type 1

Author

Nimani, S, primary, Bains, S, additional, Alerni, N, additional, Giammarino, L, additional, Louradour, J, additional, Horvath, A, additional, Beslac, O, additional, Tester, D J, additional, Christoforou, N, additional, Brunner, M, additional, Casoni, D, additional, Haeberlin, A, additional, Brooks, G, additional, Ackerman, M J, additional, and Odening, K E, additional

Published
2024
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4. In vivo KCNQ1-suppression-replacement gene therapy in transgenic rabbits with type 1 long QT syndrome

Author

Giammarino, L, primary, Nimani, S, additional, Bains, S, additional, Alerni, N, additional, Tester, D J, additional, Christoforou, N, additional, Louradour, J, additional, Jurgensen, J, additional, Barry, M A, additional, Koren, G, additional, Zehender, M, additional, Brunner, M, additional, Brooks, G, additional, Ackerman, M J, additional, and Odening, K E, additional

Published
2023
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5. Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls

Author

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

6. Prevalence and Phenotypic Correlations of Calmodulinopathy-Causative CALM1-3 Variants Detected in a Multicenter Molecular Autopsy Cohort of Sudden Unexplained Death Victims

Author

Clemens, D, Gray, B, Bagnall, R, Tester, D, Giudicessi, J, Maleszewski, J, Crotti, L, Schwartz, P, Matthews, E, Semsarian, C, Behr, E, Ackerman, M, Clemens D. J., Gray B., Bagnall R. D., Tester D. J., Giudicessi J. R., Maleszewski J. J., Crotti L., Schwartz P. J., Matthews E., Semsarian C., Behr E. R., Ackerman M. J., Clemens, D, Gray, B, Bagnall, R, Tester, D, Giudicessi, J, Maleszewski, J, Crotti, L, Schwartz, P, Matthews, E, Semsarian, C, Behr, E, Ackerman, M, Clemens D. J., Gray B., Bagnall R. D., Tester D. J., Giudicessi J. R., Maleszewski J. J., Crotti L., Schwartz P. J., Matthews E., Semsarian C., Behr E. R., and Ackerman M. J.

Published
2020

7. SCN5A mutation type and a genetic risk score associate variably with brugada syndrome phenotype in SCN5A families

Author

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.

Published
2020

8. Calmodulin mutations and life-threatening cardiac arrhythmias: Insights from the International Calmodulinopathy Registry

Author

Crotti, L, Spazzolini, C, Tester, D, Ghidoni, A, Baruteau, A, Beckmann, B, Behr, E, Bennett, J, Bezzina, C, Bhuiyan, Z, Celiker, A, Cerrone, M, Dagradi, F, De Ferrari, G, Etheridge, S, Fatah, M, Garcia-Pavia, P, Al-Ghamdi, S, Hamilton, R, Al-Hassnan, Z, Horie, M, Jimenez-Jaimez, J, Kanter, R, Kaski, J, Kotta, M, Lahrouchi, N, Makita, N, Norrish, G, Odland, H, Ohno, S, Papagiannis, J, Parati, G, Sekarski, N, Tveten, K, Vatta, M, Webster, G, Wilde, A, Wojciak, J, George, A, Ackerman, M, Schwartz, P, Crotti L., Spazzolini C., Tester D. J., Ghidoni A., Baruteau A. -E., Beckmann B. -M., Behr E. R., Bennett J. S., Bezzina C. R., Bhuiyan Z. A., Celiker A., Cerrone M., Dagradi F., De Ferrari G. M., Etheridge S. P., Fatah M., Garcia-Pavia P., Al-Ghamdi S., Hamilton R. M., Al-Hassnan Z. N., Horie M., Jimenez-Jaimez J., Kanter R. J., Kaski J. P., Kotta M. -C., Lahrouchi N., Makita N., Norrish G., Odland H. H., Ohno S., Papagiannis J., Parati G., Sekarski N., Tveten K., Vatta M., Webster G., Wilde A. A. M., Wojciak J., George A. L., Ackerman M. J., Schwartz P. J., Crotti, L, Spazzolini, C, Tester, D, Ghidoni, A, Baruteau, A, Beckmann, B, Behr, E, Bennett, J, Bezzina, C, Bhuiyan, Z, Celiker, A, Cerrone, M, Dagradi, F, De Ferrari, G, Etheridge, S, Fatah, M, Garcia-Pavia, P, Al-Ghamdi, S, Hamilton, R, Al-Hassnan, Z, Horie, M, Jimenez-Jaimez, J, Kanter, R, Kaski, J, Kotta, M, Lahrouchi, N, Makita, N, Norrish, G, Odland, H, Ohno, S, Papagiannis, J, Parati, G, Sekarski, N, Tveten, K, Vatta, M, Webster, G, Wilde, A, Wojciak, J, George, A, Ackerman, M, Schwartz, P, Crotti L., Spazzolini C., Tester D. J., Ghidoni A., Baruteau A. -E., Beckmann B. -M., Behr E. R., Bennett J. S., Bezzina C. R., Bhuiyan Z. A., Celiker A., Cerrone M., Dagradi F., De Ferrari G. M., Etheridge S. P., Fatah M., Garcia-Pavia P., Al-Ghamdi S., Hamilton R. M., Al-Hassnan Z. N., Horie M., Jimenez-Jaimez J., Kanter R. J., Kaski J. P., Kotta M. -C., Lahrouchi N., Makita N., Norrish G., Odland H. H., Ohno S., Papagiannis J., Parati G., Sekarski N., Tveten K., Vatta M., Webster G., Wilde A. A. M., Wojciak J., George A. L., Ackerman M. J., and Schwartz P. J.

Abstract

Aims: Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1-3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. Methods and results: A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1-5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0-8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. Conclusion: Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.

Published
2019

9. Transethnic genome-wide association study provides insights in the genetic architecture and heritability of long QT syndrome

Author

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

Published
2020

10. Abnormal myocardial expression of SAP97 is associated with arrhythmogenic risk

Author

Musa, H, Marcou, C, Herron, T, Makara, M, Tester, D, O'Connell, R, Rosinski, B, Guerrero-Serna, G, Milstein, M, Monteiro Da Rocha, A, Ye, D, Crotti, L, Nesterenko, V, Castelletti, S, Torchio, M, Kotta, M, Dagradi, F, Antzelevitch, C, Mohler, P, Schwartz, P, Ackerman, M, Anumonwo, J, Musa H, Marcou CA, Herron TJ, Makara M, Tester DJ, O'Connell R, Rosinski B, Guerrero-Serna G, Milstein ML, Monteiro Da Rocha A, Ye D, Crotti L, Nesterenko VV, Castelletti S, Torchio M, Kotta MC, Dagradi F, Antzelevitch C, Mohler PJ, Schwartz PJ, Ackerman MJ, Anumonwo JMB., Musa, H, Marcou, C, Herron, T, Makara, M, Tester, D, O'Connell, R, Rosinski, B, Guerrero-Serna, G, Milstein, M, Monteiro Da Rocha, A, Ye, D, Crotti, L, Nesterenko, V, Castelletti, S, Torchio, M, Kotta, M, Dagradi, F, Antzelevitch, C, Mohler, P, Schwartz, P, Ackerman, M, Anumonwo, J, Musa H, Marcou CA, Herron TJ, Makara M, Tester DJ, O'Connell R, Rosinski B, Guerrero-Serna G, Milstein ML, Monteiro Da Rocha A, Ye D, Crotti L, Nesterenko VV, Castelletti S, Torchio M, Kotta MC, Dagradi F, Antzelevitch C, Mohler PJ, Schwartz PJ, Ackerman MJ, and Anumonwo JMB.

Abstract

Abnormal myocardial expression of SAP97 is associated with arrhythmogenic risk. Am J Physiol Heart Circ Physiol 318: H1357-H1370, 2020. First published March 20, 2020; doi:10.1152/ajpheart.00481.2019.-Synapseassociated protein 97 (SAP97) is a scaffolding protein crucial for the functional expression of several cardiac ion channels and therefore proper cardiac excitability. Alterations in the functional expression of SAP97 can modify the ionic currents underlying the cardiac action potential and consequently confer susceptibility for arrhythmogenesis. In this study, we generated a murine model for inducible, cardiactargeted Sap97 ablation to investigate arrhythmia susceptibility and the underlying molecular mechanisms. Furthermore, we sought to identify human SAP97 (DLG1) variants that were associated with inherited arrhythmogenic disease. The murine model of cardiacspecific Sap97 ablation demonstrated several ECG abnormalities, pronounced action potential prolongation subject to high incidence of arrhythmogenic afterdepolarizations and notable alterations in the activity of the main cardiac ion channels. However, no DLG1 mutations were found in 40 unrelated cases of genetically elusive long QT syndrome (LQTS). Instead, we provide the first evidence implicating a gain of function in human DLG1 mutation resulting in an increase in Kv4.3 current (Ito) as a novel, potentially pathogenic substrate for Brugada syndrome (BrS). In conclusion, DLG1 joins a growing list of genes encoding ion channel interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. Dysfunction in these critical components of cardiac excitability can potentially result in fatal cardiac disease.

Published
2020

13. International Triadin Knockout Syndrome Registry: The Clinical Phenotype and Treatment Outcomes of Patients with Triadin Knockout Syndrome

Author

Clemens, D, Tester, D, Giudicessi, J, Bos, J, Rohatgi, R, Abrams, D, Balaji, S, Crotti, L, Faure, J, Napolitano, C, Priori, S, Probst, V, Rooryck-Thambo, C, Roux-Buisson, N, Sacher, F, Schwartz, P, Silka, M, Walsh, M, Ackerman, M, Clemens, DJ, Tester, DJ, Giudicessi, JR, Bos, JM, Rohatgi, RK, Abrams, DJ, Priori, SG, Schwartz, PJ, Silka, MJ, Walsh, MA, Ackerman, MJ, Clemens, D, Tester, D, Giudicessi, J, Bos, J, Rohatgi, R, Abrams, D, Balaji, S, Crotti, L, Faure, J, Napolitano, C, Priori, S, Probst, V, Rooryck-Thambo, C, Roux-Buisson, N, Sacher, F, Schwartz, P, Silka, M, Walsh, M, Ackerman, M, Clemens, DJ, Tester, DJ, Giudicessi, JR, Bos, JM, Rohatgi, RK, Abrams, DJ, Priori, SG, Schwartz, PJ, Silka, MJ, Walsh, MA, and Ackerman, MJ

Abstract

Background: Triadin knockout syndrome (TKOS) is a rare, inherited arrhythmia syndrome caused by recessive null mutations in TRDN-encoded cardiac triadin. Based previously on 5 triadin null patients, TKOS has been characterized by extensive T-wave inversions, transient QT prolongation, and severe disease expression of exercise-induced cardiac arrest in early childhood refractory to conventional therapy. Methods: We have established the International Triadin Knockout Syndrome Registry to include patients who have genetically proven homozygous/compound heterozygous TRDN null mutations. Clinical/genetic data were collected using an online survey generated through REDCap. Results: Currently, the International Triadin Knockout Syndrome Registry includes 21 patients (11 males, average age of 18 years) from 16 families. Twenty patients (95%) presented with either cardiac arrest (15, 71%) or syncope (5, 24%) at an average age of 3 years. Mild skeletal myopathy/proximal muscle weakness was noted in 6 (29%) patients. Of the 19 surviving patients, 16 (84%) exhibit T-wave inversions, and 10 (53%) have transient QT prolongation > 480 ms. Eight of 9 patients had ventricular ectopy on exercise stress testing. Thirteen (68%) patients have received implantable defibrillators. Despite various treatment strategies, 14 (74%) patients have had recurrent breakthrough cardiac events. Conclusion: TKOS is a potentially lethal disease characterized by T-wave inversions in the precordial leads, transient QT prolongation in some, and recurrent ventricular arrhythmias at a young age despite aggressive treatment. Patients displaying this phenotype should undergo TRDN genetic testing as TKOS may be a cause for otherwise unexplained cardiac arrest in young children. As gene therapy advances, enrollment into the International Triadin Knockout Syndrome Registry is encouraged to better understand TKOS and to ready a well-characterized cohort for future TRDN gene therapy trials.

Published
2019

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

Author

Baruteau, A, Kyndt, F, Behr, E, Vink, A, Lachaud, M, Joong, A, Schott, J, Horie, M, Denjoy, I, Crotti, L, Shimizu, W, Bos, J, Stephenson, E, Wong, L, Abrams, D, Davis, A, Winbo, A, Dubin, A, Sanatani, S, Liberman, L, Kaski, J, Rudic, B, Kwok, S, Rieubland, C, Tfelt-Hansen, J, Van Hare, G, Guyomarc'h-Delasalle, B, Blom, N, Wijeyeratne, Y, Gourraud, J, Le Marec, H, Ozawa, J, Fressart, V, Lupoglazoff, J, Dagradi, F, Spazzolini, C, Aiba, T, Tester, D, Zahavich, L, Beauséjour-Ladouceur, V, Jadhav, M, Skinner, J, Franciosi, S, Krahn, A, Abdelsayed, M, Ruben, P, Yung, T, Ackerman, M, Wilde, A, Schwartz, P, Probst, V, Baruteau, AE, Behr, ER, Vink, AS, Schott, JJ, Bos, JM, Stephenson, EA, Abrams, DJ, Davis, AM, Dubin, AM, Kaski, JP, Kwok, SY, Van Hare, GF, Blom, NA, Wijeyeratne, YD, Gourraud, JB, Lupoglazoff, JM, Tester, DJ, Zahavich, LA, Skinner, JR, Krahn, AD, Ruben, PC, Yung, TC, Ackerman, MJ, Wilde, AA, Schwartz, PJ, Probst, V., Baruteau, A, Kyndt, F, Behr, E, Vink, A, Lachaud, M, Joong, A, Schott, J, Horie, M, Denjoy, I, Crotti, L, Shimizu, W, Bos, J, Stephenson, E, Wong, L, Abrams, D, Davis, A, Winbo, A, Dubin, A, Sanatani, S, Liberman, L, Kaski, J, Rudic, B, Kwok, S, Rieubland, C, Tfelt-Hansen, J, Van Hare, G, Guyomarc'h-Delasalle, B, Blom, N, Wijeyeratne, Y, Gourraud, J, Le Marec, H, Ozawa, J, Fressart, V, Lupoglazoff, J, Dagradi, F, Spazzolini, C, Aiba, T, Tester, D, Zahavich, L, Beauséjour-Ladouceur, V, Jadhav, M, Skinner, J, Franciosi, S, Krahn, A, Abdelsayed, M, Ruben, P, Yung, T, Ackerman, M, Wilde, A, Schwartz, P, Probst, V, Baruteau, AE, Behr, ER, Vink, AS, Schott, JJ, Bos, JM, Stephenson, EA, Abrams, DJ, Davis, AM, Dubin, AM, Kaski, JP, Kwok, SY, Van Hare, GF, Blom, NA, Wijeyeratne, YD, Gourraud, JB, Lupoglazoff, JM, Tester, DJ, Zahavich, LA, Skinner, JR, Krahn, AD, Ruben, PC, Yung, TC, Ackerman, MJ, Wilde, AA, Schwartz, PJ, and Probst, V.

Abstract

Aims: To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve theirrisk stratification. Methods and results: A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between1990 and 2015. All patients <_16 years of age diagnosed with a genetically confirmed SCN5A mutation wereincluded in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children{55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families wereincluded; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiacconduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolatedBrugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a medianfollow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutationlocalized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation,age <_1 year at diagnosis in probands and age <_1 year at diagnosis in non-probands were independent predictorsof CE.Conclusion In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the mostprevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent riskfactors were identified, including age <_1 year at diagnosis, compound mutation, and mutation with both gain- andloss-of-function.

Published
2018

19. ORAL ABSTRACTS (1)Allied Professionals7CRYOABLATION FOR PAROXYSMAL ATRIAL FIBRILLATION - IS AN EP LAB REQUIRED?8A PATHWAY TO SAFETY - ANTICOAGULATION COMPLIANCE IN CIED PATIENTS WITH AF9UNDERSTANDING THE WAYS IN WHICH OCCUPATION IS AFFECTED BY POSTURAL TACHYCARDIA SYNDROME: A UK OCCUPATIONAL THERAPY PERSPECTIVE10DEVELOPMENT OF AN INTERGRATED SUPPORT PATHWAY FOR PATIENTS FULFILLING NICE CRITERIA FOR AN INTERNAL CARDIOVASCULAR DEBRIBRILLATOR (ICD) IN A DISTRICT GENERAL HOSPITAL11ARE CARDIOVASCULAR RISK FACTORS ALSO ASSOCIATED WITH THE INCIDENCE OF ATRIAL FIBRILLATION? A SYSTEMATIC REVIEW AND FIELD SYNOPSIS OF 23 FACTORS IN 32 INITIALLY HEALTHY COHORTS OF 20 MILLION PARTICIPANTS12BRAIN MRI FINDINGS IN PATIENTS WITH ATRIAL FIBRILLATION UNDERGOING CARDIOVERSIONBasic Science/Sudden Cardiac Death13PRELIMINARY ASSESSMENT OF THE “RE-ENTRY VULNERABILITY INDEX” AS A MARKER OF CARDIAC INSTABILITY IN THE HUMAN HEART USING WHOLE-HEART CONTACT EPICARDIAL MAPPING14OPTOGENETIC STIMULATION OF BRAINSTEM'S VAGAL PREGANGLIONIC NEURONES IS ASSOCIATED WITH NEURONAL NITRIC OXIDE SYNTHASE-DEPENDENT PROLONGATION OF VENTRICULAR EFFECTIVE REFRACTORY PERIOD15A DYNAMIC-CLAMP STUDY OF L-TYPE Ca2+ CURRENT IN RABBIT AND HUMAN ATRIAL MYOCYTES: THE CONTRIBUTION OF WINDOW ICaL TO EARLY AFTERDEPOLARISATIONS16WHOLE EXOME SEQUENCING IN SUDDEN INFANT DEATH SYNDROME17MEDIUM TERM SURVIVAL AND FAMILY SCREENING OUTCOMES IN AN IDIOPATHIC VENTRICULAR FIBRILLATION COHORT - A MULTICENTRE EXPERIENCE18CLINICAL CHARACTERISTICS OF SCD SURVIVORS WITH BRUGADA SYNDROME:- ARE SPONSANEOUS TYPE I ECG AND PREVIOUS SYNCOPE REALLY ASSOCIATED WITH HIGH RISK?

Author

Champney, F., primary, Maddock, L.J., primary, Welford, J., primary, Kemp, J., primary, Allan, V., primary, Persidskikh, Y., primary, Orini, M., primary, Ang, R., primary, Workman, A.J., primary, Wong, L., primary, Honarbakhsh, S., primary, Leong, K.M.W., primary, Silberbauer, J., additional, O'Nunain, S., additional, Gomes, J., additional, McCready, J., additional, Bostock, J., additional, Shaw, K., additional, McKenna, C., additional, Bailey, J., additional, Honarbakhsh, S., additional, Casas, J.P., additional, Wallace, J., additional, Hunter, R., additional, Schilling, R., additional, Perel, P., additional, Morley, K., additional, Banerjee, A., additional, Hemingway, H., additional, Mrochak, A., additional, Ilyina, T., additional, Goncharik, D., additional, Chasnoits, A., additional, Plashinskaya, L., additional, Taggart, P., additional, Hayward, M., additional, Lambiase, P.D., additional, Hosford, P.S., additional, Kasparov, S., additional, Tinker, A., additional, Gourine, A.V., additional, Kettlewell, S., additional, Dempster, J., additional, Colman, M.A., additional, Rankin, A.C., additional, Myles, R.C., additional, Smith, G.L., additional, Tester, D., additional, Jaye, A., additional, FitzPatrick, D., additional, Evans, M., additional, Fleming, P., additional, Jeffrey, I., additional, Cohen, M., additional, Simpson, M., additional, Ackerman, M., additional, Behr, E., additional, Srinivasan, N, additional, Kirkby, C, additional, Firman, E, additional, Tobin, L, additional, Murphy, C, additional, Lowe, M, additional, Hunter, RJ, additional, Finlay, M, additional, Schilling, RJ, additional, Lambiase, PD, additional, Ng, F.S., additional, Tomlinson, L., additional, Nuthoo, S., additional, Cajilog, E., additional, Lefroy, D.C., additional, Qureshi, N., additional, Koa-Wing, M., additional, Whinnett, Z.I., additional, Linton, N.W., additional, Davies, D.W., additional, Lim, P.B., additional, Peters, N.S., additional, Kanagaratnam, P., additional, and Varnava, A., additional

Published
2016
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20. Relationships between sleeve trial and wearer trial assessment of discomfort and objective measurements

Author

McGregor,BA, Doyle,E, Thompson,J, Naebe,M, Speijers,J, Tester,D, McGregor,BA, Doyle,E, Thompson,J, Naebe,M, Speijers,J, and Tester,D

Abstract

The relationships were investigated between the prickle discomfort scores, assessed by human response from wearer trial garment assessment, and sleeve trial, Wool ComfortMeter (WCM) and Wool HandleMeter (WHM) assessments of fabrics, and fiber diameter characteristics including mean fiber diameter (MFD). Sleeve trial assessment followed exercise, the use of a control sleeve to reduce participant variance and four sensory traits. WHM provides eight handle parameters calibrated against a panel of experts. Four scenarios were evaluated: sleeve trial assessment with MFD; sleeve trial assessment with MFD and WCM; sleeve trial assessment with MFD, WCM and WHM parameters; and sleeve trial assessment with WCM and WHM parameters. Data were analyzed using correlation and forward stepwise general linear modeling. There was no evidence that the incidence of fibers coarser than 30 µm aided the prediction of prickle discomfort once MFD had been accounted for in the models. There were significant correlations between the WCM measurement and each sleeve trial attribute. There was no significant correlation between WHM parameters and sleeve trial assessments. The sleeve trial attribute of ‘skin feel’ offers potential to improve the predictions made of wearer trial prickle discomfort when used in association of the WCM with or without data on fabric MFD. There was little evidence to support using WHM parameters with or without the WCM in predicting wearer assessed prickle discomfort of fabrics. These results indicate that the rapid evaluation of fabrics using sleeve trial assessment can provide cost effective ranking of consumer preferences.

Published
2015

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

Author

Arking, D, Pulit, S, Crotti, L, van der Harst, P, Munroe, P, Koopmann, T, Sotoodehnia, N, Rossin, E, Morley, M, Wang, X, Johnson, A, Lundby, A, Gudbjartsson, D, Noseworthy, P, Eijgelsheim, M, Bradford, Y, Tarasov, K, Dörr, M, Müller-Nurasyid, M, Lahtinen, A, Nolte, I, Smith, A, Bis, J, Isaacs, A, Newhouse, S, Evans, D, Post, W, Waggott, D, Lyytikäinen, L, Hicks, A, Eisele, L, Ellinghaus, D, Hayward, C, Navarro, P, Ulivi, S, Tanaka, T, Tester, D, Chatel, S, Gustafsson, S, Kumari, M, Morris, R, Naluai, A, Padmanabhan, S, Kluttig, A, Strohmer, B, Panayiotou, A, Torres, M, Knoflach, M, Hubacek, J, Slowikowski, K, Raychaudhuri, S, Kumar, R, Harris, T, Launer, L, Shuldiner, A, Alonso, A, Bader, J, Ehret, G, Huang, H, Kao, W, Strait, J, Macfarlane, P, Brown, M, Caulfield, M, Samani, N, Kronenberg, F, Willeit, J, Smith, J, Greiser, K, Meyer Zu Schwabedissen, H, Werdan, K, Carella, M, Zelante, L, Heckbert, S, Psaty, B, Rotter, J, Kolcic, I, Polašek, O, Wright, A, Griffin, M, Daly, M, Arnar, D, Hólm, H, Thorsteinsdottir, U, Denny, J, Roden, D, Zuvich, R, Emilsson, V, Plump, A, Larson, M, O'Donnell, C, Yin, X, Bobbo, M, D'Adamo, A, Iorio, A, Sinagra, G, Carracedo, A, Cummings, S, Nalls, M, Jula, A, Kontula, K, Marjamaa, A, Oikarinen, L, Perola, M, Porthan, K, Erbel, R, Hoffmann, P, Jöckel, K, Kälsch, H, Nöthen, M, den Hoed, M, Loos, R, Thelle, D, Gieger, C, Meitinger, T, Perz, S, Peters, A, Prucha, H, Sinner, M, Waldenberger, M, de Boer, R, Franke, L, van der Vleuten, P, Beckmann, B, Martens, E, Bardai, A, Hofman, N, Wilde, A, Behr, E, Dalageorgou, C, Giudicessi, J, Medeiros-Domingo, A, Kyndt, F, Probst, V, Ghidoni, A, Insolia, R, Hamilton, R, Scherer, S, Brandimarto, J, Margulies, K, Moravec, C, Greco, M, Fuchsberger, C, O'Connell, J, Lee, W, Watt, G, Campbell, H, Wild, S, El Mokhtari, N, Frey, N, Asselbergs, F, Mateo Leach, I, Navis, G, van den Berg, M, van Veldhuisen, D, Kellis, M, Krijthe, B, Franco, O, Hofman, A, Kors, J, Uitterlinden, A, Witteman, J, Kedenko, L, Lamina, C, Oostra, B, Abecasis, G, Lakatta, E, Mulas, A, Orrú, M, Schlessinger, D, Uda, M, Markus, M, Völker, U, Snieder, H, Spector, T, Arnlöv, J, Lind, L, Sundström, J, Syvänen, A, Kivimaki, M, Kähönen, M, Mononen, N, Raitakari, O, Viikari, J, Adamkova, V, Kiechl, S, Brion, M, Nicolaides, A, Paulweber, B, Haerting, J, Dominiczak, A, Nyberg, F, Whincup, P, Hingorani, A, Schott, J, Bezzina, C, Ingelsson, E, Ferrucci, L, Gasparini, P, Wilson, J, Rudan, I, Franke, A, Mühleisen, T, Pramstaller, P, Lehtimäki, T, Paterson, A, Parsa, A, Liu, Y, van Duijn, C, Siscovick, D, Gudnason, V, Jamshidi, Y, Salomaa, V, Felix, S, Sanna, S, Ritchie, M, Stricker, B, Stefansson, K, Boyer, L, Cappola, T, Olsen, J, Lage, K, Schwartz, P, Kääb, S, Chakravarti, A, Ackerman, M, Pfeufer, A, de Bakker, P, Newton-Cheh, C, Arking, DE, Pulit, SL, Munroe, PB, Rossin, EJ, Johnson, AD, Gudbjartsson, DF, Noseworthy, PA, Tarasov, KV, Lahtinen, AM, Nolte, IM, Smith, AV, Bis, JC, Newhouse, SJ, Evans, DS, Post, WS, Lyytikäinen, LP, Hicks, AA, Tester, DJ, Morris, RW, Naluai, AT, Panayiotou, AG, Hubacek, JA, Kumar, RD, Harris, TB, Launer, LJ, Shuldiner, AR, Bader, JS, Kao, WH, Strait, JB, Macfarlane, PW, Caulfield, MJ, Samani, NJ, Smith, JG, Greiser, KH, Heckbert, SR, Psaty, BM, Rotter, JI, Wright, AF, Daly, MJ, Arnar, DO, Denny, JC, Roden, DM, Zuvich, RL, Plump, AS, Larson, MG, O'Donnell, CJ, D'Adamo, AP, Cummings, SR, Nalls, MA, Kontula, KK, Jöckel, KH, Nöthen, MM, Loos, RJ, Thelle, DS, Sinner, MF, de Boer, RA, van der Vleuten, PA, Beckmann, BM, Wilde, AA, Behr, ER, Giudicessi, JR, Hamilton, RM, Scherer, SW, Moravec, CE, Greco, MFD, O'Connell, JR, Lee, WK, Watt, GC, Wild, SH, El Mokhtari, NE, Asselbergs, FW, van den Berg, MP, van Veldhuisen, DJ, Krijthe, BP, Franco, OH, Kors, JA, Uitterlinden, AG, Witteman, JC, Oostra, BA, Abecasis, GR, Lakatta, EG, Markus, MR, Spector, TD, Syvänen, AC, Raitakari, OT, Viikari, JS, Nicolaides, AN, Dominiczak, AF, Whincup, PH, Hingorani, AD, Schott, JJ, Bezzina, CR, Wilson, JF, Mühleisen, TW, Pramstaller, PP, Lehtimäki, TJ, Paterson, AD, van Duijn, CM, Siscovick, DS, Felix, SB, Ritchie, MD, Stricker, BH, Boyer, LA, Cappola, TP, Olsen, JV, Schwartz, PJ, Ackerman, MJ, de Bakker, PI, Arking, D, Pulit, S, Crotti, L, van der Harst, P, Munroe, P, Koopmann, T, Sotoodehnia, N, Rossin, E, Morley, M, Wang, X, Johnson, A, Lundby, A, Gudbjartsson, D, Noseworthy, P, Eijgelsheim, M, Bradford, Y, Tarasov, K, Dörr, M, Müller-Nurasyid, M, Lahtinen, A, Nolte, I, Smith, A, Bis, J, Isaacs, A, Newhouse, S, Evans, D, Post, W, Waggott, D, Lyytikäinen, L, Hicks, A, Eisele, L, Ellinghaus, D, Hayward, C, Navarro, P, Ulivi, S, Tanaka, T, Tester, D, Chatel, S, Gustafsson, S, Kumari, M, Morris, R, Naluai, A, Padmanabhan, S, Kluttig, A, Strohmer, B, Panayiotou, A, Torres, M, Knoflach, M, Hubacek, J, Slowikowski, K, Raychaudhuri, S, Kumar, R, Harris, T, Launer, L, Shuldiner, A, Alonso, A, Bader, J, Ehret, G, Huang, H, Kao, W, Strait, J, Macfarlane, P, Brown, M, Caulfield, M, Samani, N, Kronenberg, F, Willeit, J, Smith, J, Greiser, K, Meyer Zu Schwabedissen, H, Werdan, K, Carella, M, Zelante, L, Heckbert, S, Psaty, B, Rotter, J, Kolcic, I, Polašek, O, Wright, A, Griffin, M, Daly, M, Arnar, D, Hólm, H, Thorsteinsdottir, U, Denny, J, Roden, D, Zuvich, R, Emilsson, V, Plump, A, Larson, M, O'Donnell, C, Yin, X, Bobbo, M, D'Adamo, A, Iorio, A, Sinagra, G, Carracedo, A, Cummings, S, Nalls, M, Jula, A, Kontula, K, Marjamaa, A, Oikarinen, L, Perola, M, Porthan, K, Erbel, R, Hoffmann, P, Jöckel, K, Kälsch, H, Nöthen, M, den Hoed, M, Loos, R, Thelle, D, Gieger, C, Meitinger, T, Perz, S, Peters, A, Prucha, H, Sinner, M, Waldenberger, M, de Boer, R, Franke, L, van der Vleuten, P, Beckmann, B, Martens, E, Bardai, A, Hofman, N, Wilde, A, Behr, E, Dalageorgou, C, Giudicessi, J, Medeiros-Domingo, A, Kyndt, F, Probst, V, Ghidoni, A, Insolia, R, Hamilton, R, Scherer, S, Brandimarto, J, Margulies, K, Moravec, C, Greco, M, Fuchsberger, C, O'Connell, J, Lee, W, Watt, G, Campbell, H, Wild, S, El Mokhtari, N, Frey, N, Asselbergs, F, Mateo Leach, I, Navis, G, van den Berg, M, van Veldhuisen, D, Kellis, M, Krijthe, B, Franco, O, Hofman, A, Kors, J, Uitterlinden, A, Witteman, J, Kedenko, L, Lamina, C, Oostra, B, Abecasis, G, Lakatta, E, Mulas, A, Orrú, M, Schlessinger, D, Uda, M, Markus, M, Völker, U, Snieder, H, Spector, T, Arnlöv, J, Lind, L, Sundström, J, Syvänen, A, Kivimaki, M, Kähönen, M, Mononen, N, Raitakari, O, Viikari, J, Adamkova, V, Kiechl, S, Brion, M, Nicolaides, A, Paulweber, B, Haerting, J, Dominiczak, A, Nyberg, F, Whincup, P, Hingorani, A, Schott, J, Bezzina, C, Ingelsson, E, Ferrucci, L, Gasparini, P, Wilson, J, Rudan, I, Franke, A, Mühleisen, T, Pramstaller, P, Lehtimäki, T, Paterson, A, Parsa, A, Liu, Y, van Duijn, C, Siscovick, D, Gudnason, V, Jamshidi, Y, Salomaa, V, Felix, S, Sanna, S, Ritchie, M, Stricker, B, Stefansson, K, Boyer, L, Cappola, T, Olsen, J, Lage, K, Schwartz, P, Kääb, S, Chakravarti, A, Ackerman, M, Pfeufer, A, de Bakker, P, Newton-Cheh, C, Arking, DE, Pulit, SL, Munroe, PB, Rossin, EJ, Johnson, AD, Gudbjartsson, DF, Noseworthy, PA, Tarasov, KV, Lahtinen, AM, Nolte, IM, Smith, AV, Bis, JC, Newhouse, SJ, Evans, DS, Post, WS, Lyytikäinen, LP, Hicks, AA, Tester, DJ, Morris, RW, Naluai, AT, Panayiotou, AG, Hubacek, JA, Kumar, RD, Harris, TB, Launer, LJ, Shuldiner, AR, Bader, JS, Kao, WH, Strait, JB, Macfarlane, PW, Caulfield, MJ, Samani, NJ, Smith, JG, Greiser, KH, Heckbert, SR, Psaty, BM, Rotter, JI, Wright, AF, Daly, MJ, Arnar, DO, Denny, JC, Roden, DM, Zuvich, RL, Plump, AS, Larson, MG, O'Donnell, CJ, D'Adamo, AP, Cummings, SR, Nalls, MA, Kontula, KK, Jöckel, KH, Nöthen, MM, Loos, RJ, Thelle, DS, Sinner, MF, de Boer, RA, van der Vleuten, PA, Beckmann, BM, Wilde, AA, Behr, ER, Giudicessi, JR, Hamilton, RM, Scherer, SW, Moravec, CE, Greco, MFD, O'Connell, JR, Lee, WK, Watt, GC, Wild, SH, El Mokhtari, NE, Asselbergs, FW, van den Berg, MP, van Veldhuisen, DJ, Krijthe, BP, Franco, OH, Kors, JA, Uitterlinden, AG, Witteman, JC, Oostra, BA, Abecasis, GR, Lakatta, EG, Markus, MR, Spector, TD, Syvänen, AC, Raitakari, OT, Viikari, JS, Nicolaides, AN, Dominiczak, AF, Whincup, PH, Hingorani, AD, Schott, JJ, Bezzina, CR, Wilson, JF, Mühleisen, TW, Pramstaller, PP, Lehtimäki, TJ, Paterson, AD, van Duijn, CM, Siscovick, DS, Felix, SB, Ritchie, MD, Stricker, BH, Boyer, LA, Cappola, TP, Olsen, JV, Schwartz, PJ, Ackerman, MJ, and de Bakker, PI

Abstract

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

Published
2014

24. Characterization of SEMA3A-encoded semaphorin as a naturally cccurring Kv4.3 protein inhibitor and its contribution to Brugada Syndrome

Author

Boczek, N, Ye, D, Johnson, E, Wang, W, Crotti, L, Tester, D, Dagradi, F, Mizusawa, Y, Torchio, M, Alders, M, Giudicessi, J, Wilde, A, Schwartz, P, Nerbonne, J, Ackerman, M, Boczek, NJ, Johnson, EK, Tester, DJ, Giudicessi, JR, Wilde, AA, Schwartz, PJ, Nerbonne, JM, Ackerman, MJ, Boczek, N, Ye, D, Johnson, E, Wang, W, Crotti, L, Tester, D, Dagradi, F, Mizusawa, Y, Torchio, M, Alders, M, Giudicessi, J, Wilde, A, Schwartz, P, Nerbonne, J, Ackerman, M, Boczek, NJ, Johnson, EK, Tester, DJ, Giudicessi, JR, Wilde, AA, Schwartz, PJ, Nerbonne, JM, and Ackerman, MJ

Abstract

Rationale: Semaphorin 3A (SEMA3A)-encoded semaphorin is a chemorepellent that disrupts neural patterning in the nervous and cardiac systems. In addition, SEMA3A has an amino acid motif that is analogous to hanatoxin, an inhibitor of voltage-gated K+ channels. SEMA3A-knockout mice exhibit an abnormal ECG pattern and are prone to ventricular arrhythmias and sudden cardiac death. Objective: Our aim was to determine whether SEMA3A is a naturally occurring protein inhibitor of K(v)4.3 (I-to) channels and its potential contribution to Brugada syndrome. Methods and Results: K(v)4.3, Na(v)1.5, Ca(v)1.2, or K(v)4.2 were coexpressed or perfused with SEMA3A in HEK293 cells, and electrophysiological properties were examined via whole-cell patch clamp technique. SEMA3A selectively altered K(v)4.3 by significantly reducing peak current density without perturbing K(v)4.3 cell surface protein expression. SEMA3A also reduced I-to current density in cardiomyocytes derived from human-induced pluripotent stem cells. Disruption of a putative toxin binding domain on K(v)4.3 was used to assess physical interactions between SEMA3A and K(v)4.3. These findings in combination with coimmunoprecipitations of SEMA3A and K(v)4.3 revealed a potential direct binding interaction between these proteins. Comprehensive mutational analysis of SEMA3A was performed on 198 unrelated SCN5A genotype-negative patients with Brugada syndrome, and 2 rare SEMA3A missense mutations were identified. The SEMA3A mutations disrupted SEMA3A's ability to inhibit K(v)4.3 channels, resulting in a significant gain of K(v)4.3 current compared with wild-type SEMA3A. Conclusions: This study is the first to demonstrate SEMA3A as a naturally occurring protein that selectively inhibits K(v)4.3 and SEMA3A as a possible Brugada syndrome susceptibility gene through a K(v)4.3 gain-of-function mechanism

Published
2014

25. The Wool ComfortMeter and the Wool HandleMeter, new opportunities for wool

Author

[Unknown], Tester, D., McGregor, B., Wang, H., Naebe, M., Mahar, T., [Unknown], Tester, D., McGregor, B., Wang, H., Naebe, M., and Mahar, T.

Abstract

Two instruments have been developed by the Sheep CRC that provide the tools for a new standard in comfort and handle for the next generation of next-to-skin wool knitwear. The Wool ComfortMeter and Wool HandleMeter provide a rapid, accurate and objective measure of two important characteristics of wool knitwear that are currently determined by subjective assessment. The Wool HandleMeter allows the prediction of a set of handle attribute values that can quantify the hand feel of a lightweight jersey fabric. The instrument uses the principle of pushing a fabric sample through a ring. The force displacement curve associated with the fabric test is characterised and used to define each fabric. These values were then compared to the average handle values, as determined by a group of experts, of a large set of lightweight knitted fabrics. Algorithms were developed that enable the instrument to more accurately predict each of seven handle attributes than an individual expert. The Wool ComfortMeter provides a measure of the fibres that are protruding from the surface of the fabric that are responsible for the itchy sensation caused by some knitwear. The results from the instrument have been compared to the results from extensive wearer trials to provide an understanding of the relationship between the instrument value and the comfort perceptions of wearers. The results have shown a very clear relationship between the instrument and wearer trials.

Published
2013

26. Cardiac Channelopathies and Sudden Infant Death Syndrome

Author

Gussak, I, Antzelevitch, C, Wilde, AAM, Powell, BD, Ackerman, MJ, Shen, W., Schwartz, P, Stramba-Badiale, M, Giudicessi, J, Tester, D, Crotti, L, Ackerman, M, Schwartz, PJ, Giudicessi, JR, Tester, DJ, Ackerman, MJ., Gussak, I, Antzelevitch, C, Wilde, AAM, Powell, BD, Ackerman, MJ, Shen, W., Schwartz, P, Stramba-Badiale, M, Giudicessi, J, Tester, D, Crotti, L, Ackerman, M, Schwartz, PJ, Giudicessi, JR, Tester, DJ, and Ackerman, MJ.

Abstract

Sudden Infant Death Syndrome (SIDS) represents the leading cause of postneonatal sudden death in developed countries, the third leading cause of infant mortality overall in the United States, and a source of devastating psychosocial consequences for the families of victims. This chapter (i) describes the cardiac QT hypothesis for SIDS according to which some cases of SIDS might be due to ventricular fibrillation associated with prolonged repolarization, (ii) summarizes the results of an 18-year long prospective study with electrocardiogram (ECG) recordings in over 34,000 infants, (iii) discusses recent findings which provide the molecular and functional evidence linking SIDS to cardiac channelopathies like the congenital long QT syndrome (LQTS), Short QT syndrome (SQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT), (iv) presents the results of a prospective ECG study involving 45,000 infants which provided the first opportunity for a data-driven assessment of the prevalence of LQTS and summarizes the main finding of a cost-effectiveness study which analyzes a screening neonatal ECG program in a large European country, and (v) addresses the implications of 35 plus years of research on LQTS and SIDS. The studies presented here provide the conclusive evidence that genetically mediated arrhythmias represent a significant and non-dismissible cause of SIDS and support the concept of widespread neonatal ECG screening for the identification of a subset of infants at high risk for sudden death that can be prevented as it is the case with most patients affected by LQTS.

Published
2013

27. Long QT syndrome-associated mutations in intrauterine fetal death.

Author

Crotti, L, Tester, D, White, M, Bartos, D, Insolia, R, Besana, A, Kunic, J, Will, M, Velasco, E, Bair, J, Ghidoni, A, Cetin, I, Van Dyke, D, Wick, M, Brost, B, Delise, B, Facchinetti, F, George, A, Schwartz, P, Ackerman, M, Tester, DJT, White, MW, Bartos, DC, Kunic, JD, Will, ML, Velasco, EJ, Bair, JJ, Van Dyke, DL, Wick, MJ, Delise, BP, George, AL, Schwartz, PJ, Ackerman, MJ., Crotti, L, Tester, D, White, M, Bartos, D, Insolia, R, Besana, A, Kunic, J, Will, M, Velasco, E, Bair, J, Ghidoni, A, Cetin, I, Van Dyke, D, Wick, M, Brost, B, Delise, B, Facchinetti, F, George, A, Schwartz, P, Ackerman, M, Tester, DJT, White, MW, Bartos, DC, Kunic, JD, Will, ML, Velasco, EJ, Bair, JJ, Van Dyke, DL, Wick, MJ, Delise, BP, George, AL, Schwartz, PJ, and Ackerman, MJ.

Abstract

Importance: Intrauterine fetal death or stillbirth occurs in approximately 1 out of every 160 pregnancies and accounts for 50% of all perinatal deaths. Postmortem evaluation fails to elucidate an underlying cause in many cases. Long QT syndrome (LQTS) may contribute to this problem. Objective: To determine the spectrum and prevalence of mutations in the 3 most common LQTS susceptible genes (KCNQ1, KCNH2, and SCN5A) for a cohort of unexplained cases. Design, Setting, and Patients: In this case series, retrospective postmortem genetic testing was conducted on a convenience sample of 91 unexplained intrauterine fetal deaths (mean [SD] estimated gestational age at fetal death, 26.3 [8.7] weeks) that were collected from 2006-2012 by the Mayo Clinic, Rochester, Minnesota, or the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. More than 1300 ostensibly healthy individuals served as controls. In addition, publicly available exome databases were assessed for the general population frequency of identified genetic variants. Main Outcomes and Measures: Comprehensive mutational analyses of KCNQ1 (KV7.1, LQTS type 1), KCNH2 (HERG/KV11.1, LQTS type 2), and SCN5A (NaV1.5, LQTS type 3) were performed using denaturing high-performance liquid chromatography and direct DNA sequencing on genomic DNA extracted from decedent tissue. Functional analyses of novel mutations were performed using heterologous expression and patch-clamp recording. Results: The 3 putative LQTS susceptibility missense mutations (KCNQ1, p.A283T; KCNQ1, p.R397W; and KCNH2[1b], p.R25W), with a heterozygous frequency of less than 0.05% in more than 10 000 publicly available exomes and absent in more than 1000 ethnically similar control patients, were discovered in 3 intrauterine fetal deaths (3.3% [95% CI, 0.68%-9.3%]). Both K V7.1-A283T (16-week male) and KV7.1-R397W (16-week female) mutations were associated with marked KV7.1 loss-of-function consistent with in utero LQTS type 1, whereas the HERG1b-R25W muta

Published
2013

28. FGF12 is a candidate Brugada syndrome locus

Author

Hennessey, J, Marcou, C, Wang, C, Wei, E, Tester, D, Torchio, M, Dagradi, F, Crotti, L, Schwartz, P, Ackerman, M, Pitt, G, Hennessey, JA, Marcou, CA, Wei, EQ, Tester, DJ, Schwartz, PJ, Ackerman, MJ, Pitt, GS, Hennessey, J, Marcou, C, Wang, C, Wei, E, Tester, D, Torchio, M, Dagradi, F, Crotti, L, Schwartz, P, Ackerman, M, Pitt, G, Hennessey, JA, Marcou, CA, Wei, EQ, Tester, DJ, Schwartz, PJ, Ackerman, MJ, and Pitt, GS

Abstract

Background Less than 30% of the cases of Brugada syndrome (BrS) have an identified genetic cause. Of the known BrS-susceptibility genes, loss-of-function mutations in SCN5A or CACNA1C and their auxiliary subunits are most common. On the basis of the recent demonstration that fibroblast growth factor (FGF) homologous factors (FHFs; FGF11-FGF14) regulate cardiac Na + and Ca2+ channel currents, we hypothesized that FHFs are candidate BrS loci. Objective The goal of this study was to test whether FGF12 is a candidate BrS locus. Methods We used quantitative polymerase chain reaction to identify the major FHF expressed in the human ventricle and then queried a phenotype-positive, genotype-negative BrS biorepository for FHF mutations associated with BrS. We queried the effects of an identified mutant with biochemical analyses combined with electrophysiological assessment. We designed a novel rat ventricular cardiomyocyte system in which we swapped the endogenous FHF with the identified mutant and defined its effects on multiple ionic currents in their native milieu and on the cardiac action potential. Results We identified FGF12 as the major FHF expressed in the human ventricle. In 102 individuals in the biorepository, we identified a single missense mutation in FGF12-B (Q7R-FGF12). The mutant reduced binding to the NaV1.5 C terminus, but not to junctophilin-2. In adult rat cardiac myocytes, Q7R-FGF12, but not wild-type FGF12, reduced Na+ channel current density and availability without affecting Ca2+ channel function. Furthermore, the mutant, but not wild-type FGF12, reduced action potential amplitude, which is consistent with a mutant-induced loss of Na+ channel function. Conclusions These multilevel investigations strongly suggest that Q7R-FGF12 is a disease-associated BrS mutation. Moreover, these data suggest for the first time that FHF effects on Na+ and Ca2+ channels are separable. Most significantly, this study establishes a new method to analyze effects of human a

Published
2013

29. Spectrum and prevalence of mutations involving BrS1-12 susceptibility genes in a cohort of unrelated patients referred for Brugada Syndrome genetic testing: implications for genetic testing

Author

Crotti, L, Marcou, C, Tester, D, Castelletti, S, Giudicessi, J, Torchio, M, Medeiros-Domingo, A, Simone, S, Will, M, Dagradi, F, Schwartz, P, Ackerman, M, Crotti L, Marcou CA, Tester DJ, Castelletti S, Giudicessi JR, Torchio M, Medeiros-Domingo A, Simone S, Will ML, Dagradi F, Schwartz PJ, Ackerman MJ., Crotti, L, Marcou, C, Tester, D, Castelletti, S, Giudicessi, J, Torchio, M, Medeiros-Domingo, A, Simone, S, Will, M, Dagradi, F, Schwartz, P, Ackerman, M, Crotti L, Marcou CA, Tester DJ, Castelletti S, Giudicessi JR, Torchio M, Medeiros-Domingo A, Simone S, Will ML, Dagradi F, Schwartz PJ, and Ackerman MJ.

Abstract

Objectives: The aim of this study was to provide the spectrum and prevalence of mutations in the 12 Brugada syndrome (BrS)-susceptibility genes discovered to date in a single large cohort of unrelated BrS patients. Background: BrS is a potentially lethal heritable arrhythmia syndrome diagnosed electrocardiographically by coved-type ST-segment elevation in the right precordial leads (V1 to V3; type 1 Brugada electrocardiographic [ECG] pattern) and the presence of a personal/family history of cardiac events. Methods: Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing, comprehensive mutational analysis of BrS1- through BrS12-susceptibility genes was performed in 129 unrelated patients with possible/probable BrS (46 with clinically diagnosed BrS [ECG pattern plus personal/family history of a cardiac event] and 83 with a type 1 BrS ECG pattern only). Results: Overall, 27 patients (21%) had a putative pathogenic mutation, absent in 1,400 Caucasian reference alleles, including 21 patients with an SCN5A mutation, 2 with a CACNB2B mutation, and 1 each with a KCNJ8 mutation, a KCND3 mutation, an SCN1Bb mutation, and an HCN4 mutation. The overall mutation yield was 23% in the type 1 BrS ECG pattern-only patients versus 17% in the clinically diagnosed BrS patients and was significantly greater among young men <20 years of age with clinically diagnosed BrS and among patients who had a prolonged PQ interval. Conclusions: We identified putative pathogenic mutations in ∼20% of our BrS cohort, with BrS genes 2 through 12 accounting for <5%. Importantly, the yield was similar between patients with only a type 1 BrS ECG pattern and those with clinically established BrS. The yield approaches 40% for SCN5A-mediated BrS (BrS1) when the PQ interval exceeds 200 ms. Calcium channel-mediated BrS is extremely unlikely in the absence of a short QT interval

Published
2012

30. Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome

Author

Giudicessi, J, Ye, D, Tester, D, Crotti, L, Mugione, A, Nesterenko, V, Albertson, R, Antzelevitch, C, Schwartz, P, Ackerman, M, Giudicessi, JR, Tester, DJ, Nesterenko, VV, Albertson, RM, Schwartz, PJ, Ackerman, MJ, Giudicessi, J, Ye, D, Tester, D, Crotti, L, Mugione, A, Nesterenko, V, Albertson, R, Antzelevitch, C, Schwartz, P, Ackerman, M, Giudicessi, JR, Tester, DJ, Nesterenko, VV, Albertson, RM, Schwartz, PJ, and Ackerman, MJ

Abstract

Background: Brugada syndrome (BrS) is a sudden death-predisposing genetic condition characterized electrocardiographically by ST segment elevation in the leads V 1-V 3. Given the prominent role of the transient outward current (I to) in BrS pathogenesis, we hypothesized that rare gain-of-function mutations in KCND3 may serve as a pathogenic substrate for BrS. Methods: Comprehensive mutational analysis of KCND3-encoded Kv4.3 (I to) was conducted using polymerase chain reaction, denaturing high performance liquid chromatography, and direct sequencing of DNA derived from 86 unrelated BrS1-8 genotype-negative BrS patients. DNA from 780 healthy individuals was examined to assess allelic frequency for nonsynonymous variants. Putative BrS-associated Kv4.3 mutations were engineered and coexpressed with wild-type KChIP2 in HEK293 cells. Wild-type and mutant I to ion currents were recorded using whole-cell patch clamp. Results: Two BrS1-8 genotype-negative cases possessed novel Kv4.3 missense mutations. Both Kv4.3-L450F and Kv4.3-G600R were absent in 1,560 reference alleles and involved residues highly conserved across species. Both Kv4.3-L450F and Kv4.3-G600R demonstrated a gain-of-function phenotype, increasing peak I to current density by 146.2% (n = 15, P <.05) and 50.4% (n = 15, P <.05), respectively. Simulations using a Luo-Rudy II action potential (AP) model demonstrated the stable loss of the AP dome as a result of the increased I to maximal conductance associated with the heterozygous expression of either L450F or G600R. Conclusions: These findings provide the first molecular and functional evidence implicating novel KCND3 gain-of-function mutations in the pathogenesis and phenotypic expression of BrS, with the potential for a lethal arrhythmia being precipitated by a genetically enhanced I to current gradient within the right ventricle where KCND3 expression is the highest

Published
2011

31. Gain of function mutation, S422L, in the KCNJ8-encoded cardiac K ATP channel Kir6.1 as a pathogenic substrate for J wave syndromes

Author

Medeiros-Domingo, A, Tan, B, Crotti, L, Tester, D, Eckhardt, L, Cuoretti, A, Kroboth, S, Song, C, Zhou, Q, Kopp, D, Schwartz, P, Makielski, J, Ackerman, M, Medeiros-Domingo A, Tan BH, Crotti L, Tester DJ, Eckhardt L, Cuoretti A, Kroboth SL, Song C, Zhou Q, Kopp D, Schwartz PJ, Makielski JC, Ackerman MJ., Medeiros-Domingo, A, Tan, B, Crotti, L, Tester, D, Eckhardt, L, Cuoretti, A, Kroboth, S, Song, C, Zhou, Q, Kopp, D, Schwartz, P, Makielski, J, Ackerman, M, Medeiros-Domingo A, Tan BH, Crotti L, Tester DJ, Eckhardt L, Cuoretti A, Kroboth SL, Song C, Zhou Q, Kopp D, Schwartz PJ, Makielski JC, and Ackerman MJ.

Abstract

Background: J-wave syndromes have emerged conceptually to encompass the pleiotropic expression of J-point abnormalities including Brugada syndrome (BrS) and early repolarization syndrome (ERS). KCNJ8, which encodes the cardiac KATP Kir6.1 channel, recently has been implicated in ERS following identification of the functionally uncharacterized missense mutation S422L. Objective: The purpose of this study was to further explore KCNJ8 as a novel susceptibility gene for J-wave syndromes. Methods: Using polymerase chain reaction, denaturing highperformance liquid chromatography, and direct DNA sequencing, comprehensive open reading frame/splice site mutational analysis of KCNJ8 was performed in 101 unrelated patients with J-wave syndromes, including 87 with BrS and 14 with ERS. Six hundred healthy individuals were examined to assess the allelic frequency for all variants detected. KCNJ8 mutation(s) was engineered by site-directed mutagenesis and coexpressed heterologously with SUR2A in COS-1 cells. Ion currents were recorded using whole-cell configuration of the patch-clamp technique. Results: One BrS case and one ERS case hosted the identical missense mutation S422L, which was reported previously. KCNJ8-S422L involves a highly conserved residue and was absent in 1,200 reference alleles. Both cases were negative for mutations in all known BrS and ERS susceptibility genes. KATP current of the Kir6.1-S422L mutation was increased significantly over the voltage range from 0 to 40 mV compared to Kir6.1-WT channels (n = 1621; P <.05). Conclusion: These findings further implicate KCNJ8 as a novel J-wave syndrome susceptibility gene and a marked gain of function in the cardiac KATP Kir6.1 channel secondary to KCNJ8-S422L as a novel pathogenic mechanism for the phenotypic expression of both BrS and ERS

Published
2010

38. Different mechanisms underlie DNA instability in Huntington disease and colorectal cancer.

Author

Goellner, G M, Tester, D, Thibodeau, S, Almqvist, E, Goldberg, Y P, Hayden, M R, McMurray, C T, Goellner, G M, Tester, D, Thibodeau, S, Almqvist, E, Goldberg, Y P, Hayden, M R, and McMurray, C T

Abstract

Two recent lines of evidence raise the possibility that instability in germ-line or somatic cells arises by a common mechanism that involves defective mismatch repair. Mutations in mismatch-repair proteins are known to cause instability in hereditary nonpolyposis colorectal cancer, instability that is physically similar to germ-line instability observed in Huntington disease (HD). Furthermore, both germ-line and somatic-cell instability are likely to be mitotic defects, the former occurring early in embryogenesis. To test the hypothesis that defective repair is a common prerequisite for instability, we have utilized two disease groups that represent different instability "conditions." Germ-line instability within simple tandem repeats (STR) at 10 loci in 29 HD families were compared with somatic instability at the same loci in 26 colon cancer (CC) patients with identified or suspected defects in mismatch-repair enzymes. HD is known to be caused by expansion within the CAG repeat of the locus, but the extent or pattern of STR instability outside this region has not been examined systematically. We find a distinctly different pattern of STR mutation in the two disease groups, suggesting different mechanisms. Instability in HD is generally confined to a single locus, whereas instability is widespread for the same loci in CC. Our data do not support a causative role for defective mismatch-repair enzymes in instability associated with HD; rather, our data are consistent with a model in which DNA structure may inhibit normal mismatch repair at the expansion site.

Published
1997

41. Agricultural Chemicals and the Environment

Author

Barbour, Anthony K, primary, Burdett, N A, additional, Cairns Jr, John, additional, Chave, P A, additional, Crutzen, Paul, additional, Fish, Hugh, additional, Gittins, Michael J, additional, Harries, John E, additional, Hopke, Philip K, additional, Houghton, John T, additional, King, N J, additional, Matsui, Saburo, additional, Slater, David H, additional, Spiro, T G, additional, Taylor, David, additional, Warner, Frederick, additional, Codd, Geoffrey A, additional, Doyle, Peter, additional, Acamovic, T, additional, Stewart, C S, additional, Addiscott, T, additional, Fowler, D, additional, Bell, S, additional, Ferguson, A J D, additional, Pearson, M J, additional, Reynolds, C S, additional, Tester, D J, additional, Barnden, A D, additional, Eke, K, additional, and Sutton, M A, additional

Published
1996
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42. Book Review

Author

Mehta, P. V., primary, Tester, D. H., additional, and Smith, S. B., additional

Published
1996
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45. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome.

Author

Ackerman, Michael J., Siu, Benjamin L., Sturner, William Q., Tester, David J., Valdivia, Carmen R., Makielski, Jonathan C., Towbin, Jeffrey A., Ackerman, M J, Siu, B L, Sturner, W Q, Tester, D J, Valdivia, C R, Makielski, J C, and Towbin, J A

Subjects
SUDDEN infant death syndrome, GENETIC mutation, ARRHYTHMIA, INFANT death
Abstract

Context: Fatal arrhythmias from occult long QT syndrome may be responsible for some cases of sudden infant death syndrome (SIDS). Because patients who have long QT syndrome with sodium channel gene (SCN5A) defects have an increased frequency of cardiac events during sleep, and a recent case is reported of a sporadic SCN5A mutation in an infant with near SIDS, SCN5A has emerged as the leading candidate ion channel gene for SIDS.Objective: To determine the prevalence and functional properties of SCN5A mutations in SIDS.Design, Setting, and Subjects: Postmortem molecular analysis of 93 cases of SIDS or undetermined infant death identified by the Medical Examiner's Office of the Arkansas State Crime Laboratory between September 1997 and August 1999. Genomic DNA was extracted from frozen myocardium and subjected to SCN5A mutational analyses. Missense mutations were incorporated into the human heart sodium channel alpha subunit by mutagenesis, transiently transfected into human embryonic kidney cells, and characterized electrophysiologically.Main Outcome Measures: Molecular and functional characterization of SCN5A defects.Results: Two of the 93 cases of SIDS possessed SCN5A mutations: a 6-week-old white male with an A997S missense mutation in exon 17 and a 1-month old white male with an R1826H mutation in exon 28. These 2 distinct mutations occurred in highly conserved regions of the sodium channel and were absent in 400 control patients (800 alleles). Functionally, the A997S and R1826H mutant channels expressed a sodium current characterized by slower decay and a 2- to 3-fold increase in late sodium current.Conclusion: Approximately 2% of this prospective, population-based cohort of SIDS cases had an identifiable SCN5A channel defect, suggesting that mutations in cardiac ion channels may provide a lethal arrhythmogenic substrate in some infants at risk for SIDS. [ABSTRACT FROM AUTHOR]

Published
2001
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