Clinical interpretation of KCNH2 variants using a robust PS3/BS3 functional patch-clamp assay.

Matteo Vatta, Cordula M Wolf, Brett M Kroncke, Ebony Richardson, Kate L Thomson, Jodie Ingles, Chai-Ann Ng, Connie R Bezzina, Jamie I Vandenberg, Connie Jiang, Dominik S Westphal, Tobias Burkard, Steven M Harrison

Journal: HGG advances 2024;5(2):100270

PMID: 38219013

Free Full Text on Elsevier Science View on PubMed

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.

Address: Oxford Genetics Laboratories, Churchill Hospital, Oxford, UK.; Faculty of Medicine and Health, UNSW Sydney, Kensington, NSW, Australia; Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.; Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, NSW, Australia; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine and Health, Technical University of Munich, Munich, Germany; Department of Internal Medicine I, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, Munich, Germany; European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart.; Department of Congenital Heart Disease and Pediatric Cardiology, German Heart Center Munich, Technical University of Munich, School of Medicine and Health, Munich, Germany.; European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart; Department of Congenital Heart Disease and Pediatric Cardiology, German Heart Center Munich, Technical University of Munich, School of Medicine and Health, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.; Invitae Corporation, San Francisco, CA, USA.; Ambry Genetics, Aliso Viejo, CA, USA.; European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.; Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.; Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia; School of Clinical Medicine, UNSW Sydney, Darlinghurst, NSW, Australia. Electronic address: [email protected].; Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia; School of Clinical Medicine, UNSW Sydney, Darlinghurst, NSW, Australia. Electronic address: [email protected].

DOI: 10.1016/j.xhgg.2024.100270

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MeSH Terms: Child, Humans, Death, Sudden, ERG1 Potassium Channel, Heart, Long QT Syndrome, Mutation, Missense