Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controlsVisa övriga samt affilieringar
2021 (Engelska)Ingår i: Genetics in Medicine, ISSN 1098-3600, E-ISSN 1530-0366, Vol. 23, nr 1, s. 47-58Artikel i tidskrift (Refereegranskat) Published
Abstract [en]
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 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 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.
Ort, förlag, år, upplaga, sidor
Nature Publishing Group, 2021. Vol. 23, nr 1, s. 47-58
Nyckelord [en]
variant interpretation, LQTS, Brugada, ACMG/AMP guidelines
Nationell ämneskategori
Medicinsk genetik och genomik
Identifikatorer
URN: urn:nbn:se:umu:diva-175470DOI: 10.1038/s41436-020-00946-5ISI: 000566661000001PubMedID: 32893267Scopus ID: 2-s2.0-85090223596OAI: oai:DiVA.org:umu-175470DiVA, id: diva2:1472613
2020-10-022020-10-022025-02-10Bibliografiskt granskad