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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. and Whiffin, Nicola , et al. (2020) In Genetics in Medicine
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... (More)

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.

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Contribution to journal
publication status
published
subject
keywords
ACMG/AMP guidelines, Brugada, LQTS, variant interpretation
in
Genetics in Medicine
publisher
Nature Publishing Group
external identifiers
  • scopus:85090223596
  • pmid:32893267
ISSN
1098-3600
DOI
10.1038/s41436-020-00946-5
language
English
LU publication?
yes
id
794cf9bb-4c42-4c75-8806-bf5585e45050
date added to LUP
2020-09-28 10:15:46
date last changed
2024-04-17 16:16:31
@article{794cf9bb-4c42-4c75-8806-bf5585e45050,
  abstract     = {{<p>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<sup>−18</sup>) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10<sup>−13</sup>). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and &gt;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.</p>}},
  author       = {{Walsh, Roddy and Lahrouchi, Najim and Tadros, Rafik and Kyndt, Florence and Glinge, Charlotte and Postema, Pieter G. and Amin, Ahmad S. and Nannenberg, Eline A. and Ware, James S. and Whiffin, Nicola and Mazzarotto, Francesco and Škorić-Milosavljević, Doris and Krijger, Christian and Arbelo, Elena and Babuty, Dominique and Barajas-Martinez, Hector and Beckmann, Britt M. and Bézieau, Stéphane and Bos, J. Martijn and Breckpot, Jeroen and Campuzano, Oscar and Castelletti, Silvia and Celen, Candan and Clauss, Sebastian and Corveleyn, Anniek and Crotti, Lia and Dagradi, Federica and de Asmundis, Carlo and Denjoy, Isabelle and Dittmann, Sven and Ellinor, Patrick T. and Ortuño, Cristina Gil and Giustetto, Carla and Gourraud, Jean Baptiste and Hazeki, Daisuke and Horie, Minoru and Ishikawa, Taisuke and Itoh, Hideki and Kaneko, Yoshiaki and Kanters, Jørgen K. and Kimoto, Hiroki and Kotta, Maria Christina and Krapels, Ingrid P.C. and Kurabayashi, Masahiko and Lazarte, Julieta and Leenhardt, Antoine and Loeys, Bart L. and Lundin, Catarina and Makiyama, Takeru and Platonov, Pyotr G.}},
  issn         = {{1098-3600}},
  keywords     = {{ACMG/AMP guidelines; Brugada; LQTS; variant interpretation}},
  language     = {{eng}},
  month        = {{09}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Genetics in Medicine}},
  title        = {{Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls}},
  url          = {{http://dx.doi.org/10.1038/s41436-020-00946-5}},
  doi          = {{10.1038/s41436-020-00946-5}},
  year         = {{2020}},
}