Thomson, Kate L. and Jiang, Connie and Richardson, Ebony and Westphal, Dominik S. and Burkard, Tobias and Wolf, Cordula M. and Vatta, Matteo and Harrison, Steven M. and Ingles, Jodie and Bezzina, Connie R. and Kroncke, Brett M. and Vandenberg, Jamie I. and Ng, Chai-Ann (2024) Clinical interpretation of KCNH2 variants using a robust PS3/BS3 functional patch-clamp assay. Human Genetics and Genomics Advances, 5 (2). p. 100270. ISSN 26662477
Full text not available from this repository.Abstract
Long QT syndrome (LQTS), caused by the dysfunction of cardiac ion channels, increases the risk of sudden death in otherwise healthy young people. For many variants in LQTS genes, there is insufficient evidence to make a definitive genetic diagnosis. We have established a robust functional patch-clamp assay to facilitate classification of missense variants in KCNH2, one of the key LQTS genes. A curated set of 30 benign and 30 pathogenic missense variants were used to establish the range of normal and abnormal function. The extent to which variants reduced protein function was quantified using Z scores, the number of standard deviations from the mean of the normalized current density of the set of benign variant controls. A Z score of -2 defined the threshold for abnormal loss of function, which corresponds to 55% wild-type function. More extreme Z scores were observed for variants with a greater loss-of-function effect. We propose that the Z score for each variant can be used to inform the application and weighting of abnormal and normal functional evidence criteria (PS3 and BS3) within the American College of Medical Genetics and Genomics variant classification framework. The validity of this approach was demonstrated using a series of 18 KCNH2 missense variants detected in a childhood onset LQTS cohort, where the level of function assessed using our assay correlated to the Schwartz score (a scoring system used to quantify the probability of a clinical diagnosis of LQTS) and the length of the corrected QT (QTc) interval.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 16 Dec 2024 04:18 |
| Last Modified: | 16 Dec 2024 04:18 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/1537 |
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