TY - JOUR
T1 - Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls
AU - Nantes Referral Ctr Inherited Car
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 - Skoric-Milosavljevic, Doris
AU - Krijger, Christian
AU - Arbelo, Elena
AU - Babuty, Dominique
AU - Barajas-Martinez, Hector
AU - Beckmann, Britt M.
AU - Bezieau, Stephane
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 - Ortuno, 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, Jorgen 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 - van der Zwaag, Paul A.
AU - van den Berg, Maarten P.
PY - 2021/1
Y1 - 2021/1
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 - variant interpretation
KW - LQTS
KW - Brugada
KW - ACMG/AMP guidelines
KW - MUTATIONS
U2 - 10.1038/s41436-020-00946-5
DO - 10.1038/s41436-020-00946-5
M3 - Article
C2 - 32893267
SN - 1098-3600
SP - 47
EP - 58
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 1
ER -