Research
Print page Print page
Switch language
Rigshospitalet - a part of Copenhagen University Hospital
Published

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

Research output: Contribution to journalJournal articleResearchpeer-review

  1. DLG4-related synaptopathy: a new rare brain disorder

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. DOORS syndrome and a recurrent truncating ATP6V1B2 variant

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Atrial fibrillation-a complex polygenetic disease

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Witnessed and unwitnessed sudden cardiac death: a nationwide study of persons aged 1-35 years

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Cardiac arrhythmias in patients hospitalized with COVID-19: The ACOVID study

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Electrocardiographic T-wave morphology and risk of mortality

    Research output: Contribution to journalJournal articleResearchpeer-review

  • Nantes Referral Center for inherited cardiac arrhythmia
View graph of relations

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.

Original languageEnglish
JournalGenetics in medicine : official journal of the American College of Medical Genetics
Volume23
Issue number1
Pages (from-to)47-58
Number of pages12
ISSN1098-3600
DOIs
Publication statusPublished - Jan 2021

    Research areas

  • ACMG/AMP guidelines, Brugada, LQTS, variant interpretation

ID: 62374439