Multiplexed Assays of Variant Effect and Automated Patch Clamping Improve KCNH2 -LQTS Variant Classification and Cardiac Event Risk Stratification.

Autor:	O'Neill MJ; Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN (M.J.O., X.B.)., Ng CA; Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, Australia (C.-A.N., Q.S., C.-Y.T., J.I.V.)., Aizawa T; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan (T.A., A.K.)., Sala L; IRCCS, Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.S., L.C., F.D., G.M., C.S., P.J.S.).; Department of Biotechnology and Biosciences, (L.S.), University of Milano-Bicocca, Milan, Italy., Bains S; Department of Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (S.B., R.N., J.M.B., J.R.G., M.J.A.)., Winbo A; Department of Physiology (A.W., B.M.K.), University of Auckland, New Zealand., Ullah R; Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN., Shen Q; Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, Australia (C.-A.N., Q.S., C.-Y.T., J.I.V.)., Tan CY; School of Clinical Medicine, University of New South Wales Sydney, Darlinghurst, New South Wales, Australia (C.-A.N., J.I.V.)., Kozek K; Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN., Vanags LR; Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN., Mitchell DW; Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN., Shen A; Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN., Wada Y; Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN., Kashiwa A; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan (T.A., A.K.)., Crotti L; IRCCS, Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.S., L.C., F.D., G.M., C.S., P.J.S.).; Department of Medicine and Surgery (L.C.), University of Milano-Bicocca, Milan, Italy., Dagradi F; IRCCS, Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.S., L.C., F.D., G.M., C.S., P.J.S.)., Musu G; IRCCS, Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.S., L.C., F.D., G.M., C.S., P.J.S.)., Spazzolini C; IRCCS, Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.S., L.C., F.D., G.M., C.S., P.J.S.)., Neves R; Department of Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (S.B., R.N., J.M.B., J.R.G., M.J.A.)., Bos JM; Department of Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (S.B., R.N., J.M.B., J.R.G., M.J.A.)., Giudicessi JR; Department of Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (S.B., R.N., J.M.B., J.R.G., M.J.A.)., Bledsoe X; Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN (M.J.O., X.B.)., Gamazon ER; Division of Genetic Medicine (E.R.G.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN., Lancaster MC; Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN., Glazer AM; Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN., Knollmann BC; Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN., Roden DM; Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN., Weile J; Department of Medicine and Surgery, University Milano Bicocca, Milan, Italy. Department of Molecular Genetics, University of Toronto, Canada (J.W., F.R.)., Roth F; Department of Medicine and Surgery, University Milano Bicocca, Milan, Italy. Department of Molecular Genetics, University of Toronto, Canada (J.W., F.R.)., Salem JE; Sorbonne University, APHP, INSERM, Clinical Pharmacology, Hopital Pitié-Salpétière Department of Medicine (J.-E.S.), University of Auckland, New Zealand., Earle N; Department of Cardiology, Waikato Hospital, Hamilton, New Zealand (N.E., R.S.)., Stiles R; Department of Cardiology, Waikato Hospital, Hamilton, New Zealand (N.E., R.S.)., Agee T; Department of Chemistry, Mississippi State University, Starkville (T.A., C.N.J.)., Johnson CN; Department of Chemistry, Mississippi State University, Starkville (T.A., C.N.J.)., Horie M; Department of Cardiovascular Medicine, Shiga University of Medical Science, Japan (M.H.)., Skinner JR; Sydney Children's Hospital Network, University of Sydney, Australia (J.R.S.)., Ackerman MJ; Department of Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (S.B., R.N., J.M.B., J.R.G., M.J.A.)., Schwartz PJ; IRCCS, Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.S., L.C., F.D., G.M., C.S., P.J.S.)., Ohno S; Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Osaka, Japan (S.O.)., Vandenberg JI; Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, Australia (C.-A.N., Q.S., C.-Y.T., J.I.V.)., Kroncke BM; Department of Physiology (A.W., B.M.K.), University of Auckland, New Zealand.
Jazyk:	angličtina
Zdroj:	Circulation [Circulation] 2024 Dec 03; Vol. 150 (23), pp. 1869-1881. Date of Electronic Publication: 2024 Sep 24.
DOI:	10.1161/CIRCULATIONAHA.124.069828
Abstrakt:	Background: Long QT syndrome is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by KCNH2 . Variant classification is difficult, often because of lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance. Here we sought to test whether variant-specific information, primarily from high-throughput functional assays, could improve both classification and cardiac event risk stratification in a large, harmonized cohort of KCNH2 missense variant heterozygotes. Methods: We quantified cell-surface trafficking of 18 796 variants in KCNH2 using a multiplexed assay of variant effect (MAVE). We recorded KCNH2 current density for 533 variants by automated patch clamping. We calibrated the strength of evidence of MAVE data according to ClinGen guidelines. We deeply phenotyped 1458 patients with KCNH2 missense variants, including QTc, cardiac event history, and mortality. We correlated variant functional data and Bayesian long QT syndrome penetrance estimates with cohort phenotypes and assessed hazard ratios for cardiac events. Results: Variant MAVE trafficking scores and automated patch clamping peak tail currents were highly correlated (Spearman rank-order ρ=0.69; n=433). The MAVE data were found to provide up to pathogenic very strong evidence for severe loss-of-function variants. In the cohort, both functional assays and Bayesian long QT syndrome penetrance estimates were significantly predictive of cardiac events when independently modeled with patient sex and corrected QT interval (QTc); however, MAVE data became nonsignificant when peak tail current and penetrance estimates were also available. The area under the receiver operator characteristic curve for 20-year event outcomes based on patient-specific sex and QTc (area under the curve, 0.80 [0.76-0.83]) was improved with prospectively available penetrance scores conditioned on MAVE (area under the curve, 0.86 [0.83-0.89]) or attainable automated patch clamping peak tail current data (area under the curve, 0.84 [0.81-0.88]). Conclusions: High-throughput KCNH2 variant MAVE data meaningfully contribute to variant classification at scale, whereas long QT syndrome penetrance estimates and automated patch clamping peak tail current measurements meaningfully contribute to risk stratification of cardiac events in patients with heterozygous KCNH2 missense variants. Competing Interests: None.
Databáze:	MEDLINE
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