Ma, Joanne G. and O’Neill, Matthew J. and Richardson, Ebony and Thomson, Kate L. and Ingles, Jodie and Muhammad, Ayesha and Solus, Joseph F. and Davogustto, Giovanni and Anderson, Katherine C. and Shoemaker, M. Benjamin and Stergachis, Andrew B. and Floyd, Brendan J. and Dunn, Kyla and Parikh, Victoria N. and Chubb, Henry and Perrin, Mark J. and Roden, Dan M. and Vandenberg, Jamie I. and Ng, Chai-Ann and Glazer, Andrew M. (2024) Multisite Validation of a Functional Assay to Adjudicate SCN5A Brugada Syndrome–Associated Variants. Circulation: Genomic and Precision Medicine, 17 (4). ISSN 2574-8300
Full text not available from this repository.Abstract
BACKGROUND: Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in SCN5A. Interpreting the pathogenicity of SCN5A missense variants is challenging, and approximately 79% of SCN5A missense variants in ClinVar are currently classified as variants of uncertain significance. Automated patch clamp technology enables high-throughput functional studies of ion channel variants and can provide evidence for variant reclassification. METHODS: An in vitro SCN5A-Brugada syndrome automated patch clamp assay was independently performed at Vanderbilt University Medical Center and Victor Chang Cardiac Research Institute. The assay was calibrated according to ClinGen Sequence Variant Interpretation recommendations using high-confidence variant controls (n=49). Normal and abnormal ranges of function were established based on the distribution of benign variant assay results. Odds of pathogenicity values were derived from the experimental results according to ClinGen Sequence Variant Interpretation recommendations. The calibrated assay was then used to study SCN5A variants of uncertain significance observed in 4 families with Brugada syndrome and other arrhythmia phenotypes associated with SCN5A loss-of-function. RESULTS: Variant channel parameters generated independently at the 2 research sites showed strong correlations, including peak I(Na) density (R(2)=0.86). The assay accurately distinguished benign controls (24/25 concordant variants) from pathogenic controls (23/24 concordant variants). Odds of pathogenicity values were 0.042 for normal function and 24.0 for abnormal function, corresponding to strong evidence for both American College of Medical Genetics and Genomics/Association for Molecular Pathology benign and pathogenic functional criteria (BS3 and PS3, respectively). Application of the assay to 4 clinical SCN5A variants of uncertain significance revealed loss-of-function for 3/4 variants, enabling reclassification to likely pathogenic. CONCLUSIONS: This validated high-throughput assay provides clinical-grade functional evidence to aid the classification of current and future SCN5A-Brugada syndrome variants of uncertain significance.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 29 Dec 2024 04:09 |
| Last Modified: | 29 Dec 2024 04:09 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/1589 |
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