Journal article
Genetics in Medicine, 2020
APA
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Walsh, R., Lahrouchi, N., Tadros, R., Kyndt, F., Glinge, C., Postema, P., … Bezzina, C. (2020). Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. Genetics in Medicine.
Chicago/Turabian
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Walsh, R., N. Lahrouchi, R. Tadros, F. Kyndt, C. Glinge, P. Postema, A. Amin, et al. “Enhancing Rare Variant Interpretation in Inherited Arrhythmias through Quantitative Analysis of Consortium Disease Cohorts and Population Controls.” Genetics in Medicine (2020).
MLA
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Walsh, R., et al. “Enhancing Rare Variant Interpretation in Inherited Arrhythmias through Quantitative Analysis of Consortium Disease Cohorts and Population Controls.” Genetics in Medicine, 2020.
BibTeX Click to copy
@article{r2020a,
title = {Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls},
year = {2020},
journal = {Genetics in Medicine},
author = {Walsh, R. and Lahrouchi, N. and Tadros, R. and Kyndt, F. and Glinge, C. and Postema, P. and Amin, A. and Nannenberg, E. and Ware, J. and Whiffin, N. and Mazzarotto, F. and Škorić-Milosavljević, Doris and Krijger, C. and Arbelo, E. and Babuty, D. and Barajas-Martinez, H. and Beckmann, B. and Bézieau, S. and Bos, J. and Breckpot, J. and Campuzano, Ó. and Castelletti, S. and Celen, Candan and Clauss, S. and Corveleyn, A. and Crotti, L. and Dagradi, F. and de Asmundis, C. and Denjoy, I. and Dittmann, S. and Ellinor, P. and Ortuño, Cristina Gil and Giustetto, C. and Gourraud, J. and Hazeki, Daisuke and Horie, M. and Ishikawa, T. and Itoh, H. and Kaneko, Y. and Kanters, J. and Kimoto, Hiroki and Kotta, M. and Krapels, I. and Kurabayashi, M. and Lazarte, J. and Leenhardt, A. and Loeys, B. and Lundin, C. and Makiyama, T. and Mansourati, J. and Martins, Raphael P. and Mazzanti, A. and Mörner, S. and Napolitano, C. and Ohkubo, Kimie and Papadakis, M. and Rudic, B. and Molina, M. S. and Sacher, F. and Şahin, H. and Sarquella-Brugada, G. and Sebastiano, R. and Sharma, Sanjay and Sheppard, M. and Shimamoto, K. and Shoemaker, M. and Stallmeyer, B. and Steinfurt, J. and Tanaka, Yuji and Tester, D. and Usuda, K. and van der Zwaag, P. A. and Dooren, S. Van and Laer, L. Van and Winbo, A. and Winkel, B. and Yamagata, K. and Zumhagen, S. and Volders, P. and Lubitz, S. and Antzelevitch, C. and Platonov, P. and Odening, K. and Roden, D. and Roberts, Jason D. and Skinner, J. and Tfelt‐Hansen, J. and van den Berg, M. P. and Olesen, M. and Lambiase, P. and Borggrefe, M. and Hayashi, Kenshi and Rydberg, A. and Nakajima, T. and Yoshinaga, M. and Saenen, J. and Kääb, S. and Brugada, P. and Robyns, T. and Giachino, D. and Ackerman, M. and Brugada, R. and Brugada, J. and Gimeno, J. and Hasdemir, C. and Guicheney, P. and Priori, S. and Schulze-Bahr, E. and Makita, N. and Schwartz, P. and Shimizu, W. and Aiba, T. and Schott, J. and Redon, R. and Ohno, S. and Probst, V. and Jesel, Alain Al Mathieu Frédéric Olivier Pascal Jean-Marc Laure Arnaout Amelot Anselme Billon Defaye Dupuis and Arnaout, A. A. and Amelot, Mathieu and Anselme, F. and Billon, O. and Defaye, P. and Dupuis, Jean and Jesel, L. and Laurent, G. and Maury, P. and Pasquié, J. and Wiart, F. and Behr, E. and Barc, J. and Bezzina, C.}
}
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.