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

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Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. / Walsh, Roddy; Lahrouchi, Najim; Tadros, Rafik; Kyndt, Florence; Glinge, Charlotte; Postema, Pieter G.; Amin, Ahmad S.; Nannenberg, Eline A.; Ware, James S.; Whiffin, Nicola; Mazzarotto, Francesco; Škorić-Milosavljević, Doris; Krijger, Christian; Arbelo, Elena; Babuty, Dominique; Barajas-Martinez, Hector; Beckmann, Britt M.; Bézieau, Stéphane; Bos, J. Martijn; Breckpot, Jeroen; Campuzano, Oscar; Castelletti, Silvia; Celen, Candan; Clauss, Sebastian; Corveleyn, Anniek; Crotti, Lia; Dagradi, Federica; de Asmundis, Carlo; Denjoy, Isabelle; Dittmann, Sven; Ellinor, Patrick T.; Ortuño, Cristina Gil; Giustetto, Carla; Gourraud, Jean Baptiste; Hazeki, Daisuke; Horie, Minoru; Ishikawa, Taisuke; Itoh, Hideki; Kaneko, Yoshiaki; Kanters, Jørgen K.; Kimoto, Hiroki; Kotta, Maria Christina; Krapels, Ingrid P.C.; Kurabayashi, Masahiko; Lazarte, Julieta; Leenhardt, Antoine; Loeys, Bart L.; Lundin, Catarina; Makiyama, Takeru; Platonov, Pyotr G.; Nantes Referral Center for inherited cardiac arrhythmia.

In: Genetics in Medicine, 07.09.2020.

Research output: Contribution to journalArticle

Harvard

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, JB, Hazeki, D, Horie, M, Ishikawa, T, Itoh, H, Kaneko, Y, Kanters, JK, Kimoto, H, Kotta, MC, Krapels, IPC, Kurabayashi, M, Lazarte, J, Leenhardt, A, Loeys, BL, Lundin, C, Makiyama, T, Platonov, PG & Nantes Referral Center for inherited cardiac arrhythmia 2020, 'Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls', Genetics in Medicine. https://doi.org/10.1038/s41436-020-00946-5

APA

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., Škorić-Milosavljević, D., Krijger, C., Arbelo, E., Babuty, D., Barajas-Martinez, H., Beckmann, B. M., Bézieau, S., Bos, J. M., ... Nantes Referral Center for inherited cardiac arrhythmia (2020). Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. Genetics in Medicine. https://doi.org/10.1038/s41436-020-00946-5

CBE

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 JB, Hazeki D, Horie M, Ishikawa T, Itoh H, Kaneko Y, Kanters JK, Kimoto H, Kotta MC, Krapels IPC, Kurabayashi M, Lazarte J, Leenhardt A, Loeys BL, Lundin C, Makiyama T, Platonov PG, Nantes Referral Center for inherited cardiac arrhythmia. 2020. Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. Genetics in Medicine. https://doi.org/10.1038/s41436-020-00946-5

MLA

Vancouver

Author

Walsh, Roddy ; Lahrouchi, Najim ; Tadros, Rafik ; Kyndt, Florence ; Glinge, Charlotte ; Postema, Pieter G. ; Amin, Ahmad S. ; Nannenberg, Eline A. ; Ware, James S. ; Whiffin, Nicola ; Mazzarotto, Francesco ; Škorić-Milosavljević, Doris ; Krijger, Christian ; Arbelo, Elena ; Babuty, Dominique ; Barajas-Martinez, Hector ; Beckmann, Britt M. ; Bézieau, Stéphane ; Bos, J. Martijn ; Breckpot, Jeroen ; Campuzano, Oscar ; Castelletti, Silvia ; Celen, Candan ; Clauss, Sebastian ; Corveleyn, Anniek ; Crotti, Lia ; Dagradi, Federica ; de Asmundis, Carlo ; Denjoy, Isabelle ; Dittmann, Sven ; Ellinor, Patrick T. ; Ortuño, Cristina Gil ; Giustetto, Carla ; Gourraud, Jean Baptiste ; Hazeki, Daisuke ; Horie, Minoru ; Ishikawa, Taisuke ; Itoh, Hideki ; Kaneko, Yoshiaki ; Kanters, Jørgen K. ; Kimoto, Hiroki ; Kotta, Maria Christina ; Krapels, Ingrid P.C. ; Kurabayashi, Masahiko ; Lazarte, Julieta ; Leenhardt, Antoine ; Loeys, Bart L. ; Lundin, Catarina ; Makiyama, Takeru ; Platonov, Pyotr G. ; Nantes Referral Center for inherited cardiac arrhythmia. / Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. In: Genetics in Medicine. 2020.

RIS

TY - JOUR

T1 - Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls

AU - Walsh, Roddy

AU - Lahrouchi, Najim

AU - Tadros, Rafik

AU - Kyndt, Florence

AU - Glinge, Charlotte

AU - Postema, Pieter G.

AU - Amin, Ahmad S.

AU - Nannenberg, Eline A.

AU - Ware, James S.

AU - Whiffin, Nicola

AU - Mazzarotto, Francesco

AU - Škorić-Milosavljević, Doris

AU - Krijger, Christian

AU - Arbelo, Elena

AU - Babuty, Dominique

AU - Barajas-Martinez, Hector

AU - Beckmann, Britt M.

AU - Bézieau, Stéphane

AU - Bos, J. Martijn

AU - Breckpot, Jeroen

AU - Campuzano, Oscar

AU - Castelletti, Silvia

AU - Celen, Candan

AU - Clauss, Sebastian

AU - Corveleyn, Anniek

AU - Crotti, Lia

AU - Dagradi, Federica

AU - de Asmundis, Carlo

AU - Denjoy, Isabelle

AU - Dittmann, Sven

AU - Ellinor, Patrick T.

AU - Ortuño, Cristina Gil

AU - Giustetto, Carla

AU - Gourraud, Jean Baptiste

AU - Hazeki, Daisuke

AU - Horie, Minoru

AU - Ishikawa, Taisuke

AU - Itoh, Hideki

AU - Kaneko, Yoshiaki

AU - Kanters, Jørgen K.

AU - Kimoto, Hiroki

AU - Kotta, Maria Christina

AU - Krapels, Ingrid P.C.

AU - Kurabayashi, Masahiko

AU - Lazarte, Julieta

AU - Leenhardt, Antoine

AU - Loeys, Bart L.

AU - Lundin, Catarina

AU - Makiyama, Takeru

AU - Platonov, Pyotr G.

AU - Nantes Referral Center for inherited cardiac arrhythmia

PY - 2020/9/7

Y1 - 2020/9/7

N2 - 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.

AB - 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.

KW - ACMG/AMP guidelines

KW - Brugada

KW - LQTS

KW - variant interpretation

UR - http://www.scopus.com/inward/record.url?scp=85090223596&partnerID=8YFLogxK

U2 - 10.1038/s41436-020-00946-5

DO - 10.1038/s41436-020-00946-5

M3 - Article

AN - SCOPUS:85090223596

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

ER -