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; ... (2021). Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. Genetics in medicine, 23(1), pp. 47-58. Springer Nature 10.1038/s41436-020-00946-5

[img]
Preview
Text
Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.pdf - Published Version
Available under License Creative Commons: Attribution-Noncommercial-No Derivative Works (CC-BY-NC-ND).

Download (2MB) | Preview

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology

UniBE Contributor:

Odening, Katja Elisabeth

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1530-0366

Publisher:

Springer Nature

Language:

English

Submitter:

Nadia Biscozzo

Date Deposited:

07 Dec 2020 16:42

Last Modified:

11 Mar 2021 22:31

Publisher DOI:

10.1038/s41436-020-00946-5

PubMed ID:

32893267

Uncontrolled Keywords:

ACMG/AMP guidelines Brugada LQTS variant interpretation

BORIS DOI:

10.7892/boris.147831

URI:

https://boris.unibe.ch/id/eprint/147831

Actions (login required)

Edit item Edit item
Provide Feedback