An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition
| Autor: | Julia Cadrin-Tourigny, Dan M. Roden, Valentina Kutyifa, Henry J. Duff, Robert M. Gow, Marco V Perez, Eric Vittinghoff, Wataru Shimizu, Birgit Stallmeyer, Linda M. Knight, Lia Crotti, Michael H. Gollob, Silvia G. Priori, Rafik Tadros, Juan Pablo Kaski, Gregory M. Marcus, S. Yukiko Asaki, Thomas M. Roston, Sharmila Udupa, Takeshi Aiba, Deni Kukavica, Peter J. Schwartz, Nikhil Chavali, M. Benjamin Shoemaker, Carla Spazzolini, Christopher S. Simpson, Fabrizio Drago, Yanushi D. Wijeyeratne, J. Martijn Bos, Sven Dittmann, John R. Giudicessi, Eric Schulze-Bahr, Peter S. Fischbach, Anwar Baban, Keiko Shimamoto, Arthur A. M. Wilde, Jonathan R. Skinner, Jason D. Roberts, Brynn E. Dechert, Peter F. Aziz, Andrew P. Landstrom, Andrea Mazzanti, Elijah R. Behr, Jacob Tfelt-Hansen, Dominic Abrams, Elizabeth S. Kaufman, Izabela Tuleta, Alison Muir, Maisoon D. Yousif, Lorne J. Gula, Michael J. Ackerman, Wojciech Zareba, Imane El Hajjaji, Christopher L. Johnsrude, Melvin M. Scheinman, Susan P. Etheridge, Peter Leong-Sit, Luciana Marcondes, Andrew D. Krahn |
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| Přispěvatelé: | Cardiology, ACS - Heart failure & arrhythmias, Roberts, J, Asaki, S, Mazzanti, A, Bos, J, Tuleta, I, Muir, A, Crotti, L, Krahn, A, Kutyifa, V, Shoemaker, M, Johnsrude, C, Aiba, T, Marcondes, L, Baban, A, Udupa, S, Dechert, B, Fischbach, P, Knight, L, Vittinghoff, E, Kukavica, D, Stallmeyer, B, Giudicessi, J, Spazzolini, C, Shimamoto, K, Tadros, R, Cadrin-Tourigny, J, Duff, H, Simpson, C, Roston, T, Wijeyeratne, Y, El Hajjaji, I, Yousif, M, Gula, L, Leong-Sit, P, Chavali, N, Landstrom, A, Marcus, G, Dittmann, S, Wilde, A, Behr, E, Tfelt-Hansen, J, Scheinman, M, Perez, M, Kaski, J, Gow, R, Drago, F, Aziz, P, Abrams, D, Gollob, M, Skinner, J, Shimizu, W, Kaufman, E, Roden, D, Zareba, W, Schwartz, P, Schulze-Bahr, E, Etheridge, S, Priori, S, Ackerman, M |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Proband Potassium Channels Penetrance Cardiorespiratory Medicine and Haematology 030204 cardiovascular system & hematology Cardiovascular Sudden cardiac death Electrocardiography 0302 clinical medicine Genotype 2.1 Biological and endogenous factors Medicine genetics Registries Aetiology 0303 health sciences Hazard ratio Voltage-Gated Middle Aged Death Heart Disease Public Health and Health Services Female Cardiology and Cardiovascular Medicine Cardiac Adult medicine.medical_specialty Adolescent Long QT syndrome Clinical Trials and Supportive Activities Clinical Sciences Electric Countershock BIO/18 - GENETICA arrhythmia QT interval Article sudden cardiac death 03 medical and health sciences Clinical Research Physiology (medical) Internal medicine Genetics long QT syndrome Humans penetrance 030304 developmental biology business.industry Proportional hazards model Human Genome MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE medicine.disease Sudden Heart Arrest Cardiovascular System & Hematology genetic business |
| Zdroj: | Circulation, 141(6), 429-439. Lippincott Williams and Wilkins Circulation Circulation, vol 141, iss 6 |
| ISSN: | 0009-7322 1524-4539 |
| Popis: | Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P P =0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3–10.8], P =0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients. |
| Databáze: | OpenAIRE |
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