ArticleCirculation. Genomic and precision medicine2018
High-Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance.
Article in Circulation. Genomic and precision medicine, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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Who cites it
65 citing papers in PubMed, 105 citations in OpenAlex.
- Article
- High-throughput screening identifies a trafficking corrector for long QT syndrome-associated KCNQ1 variants.JCI insight · 2026Article
- Creating an atlas of variant effects to resolve variants of uncertain significance and guide cardiovascular medicine.Nature reviews. Cardiology · 2026Review
- High-Throughput Methods for Variant Functional Assessment in Cardiac Disease.Circulation. Genomic and precision medicine · 2026Review
- Case Report Series: Genetic and clinical characterization of long QT syndrome in admixed Ecuadorian patients and its implications for sudden cardiac death risk.Frontiers in cardiovascular medicine · 2026Article
- Mapping the Functional Landscape ofmedRxiv : the preprint server for health sciences · 2025Article
- Functional Profiling ofCirculation. Genomic and precision medicine · 2025Article
- High Throughput Screening Identifies a Small Molecule Trafficking Corrector for Long-QT Syndrome Associated KCNQ1 Variants.bioRxiv : the preprint server for biology · 2025Article
- Machine learning-based penetrance of genetic variants.Science (New York, N.Y.) · 2025Article
- Predicting the Damaging Potential of UncharacterizedInternational journal of molecular sciences · 2025Article
- Appropriate time interval to update ambiguous genetic diagnosis in inherited arrhythmogenic syndromes.iScience · 2025Article
- Integrative analysis of KCNQ1 variants reveals molecular mechanisms of type 1 long QT syndrome pathogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Genetic Background and Clinical Phenotype in an Italian Cohort with Inherited Arrhythmia Syndromes and Arrhythmogenic Cardiomyopathy (ACM): A Whole-Exome Sequencing Study.International journal of molecular sciences · 2025Article
- Multisite Validation of a Functional Assay to AdjudicateCirculation. Genomic and precision medicine · 2024Article
- Broadening the Genetic Spectrum of Painful Small-Fiber Neuropathy through Whole-Exome Study in Early-Onset Cases.International journal of molecular sciences · 2024Article
- Molecular and cellular context influences SCN8A variant function.JCI insight · 2024Article
- Multi-site validation of a functional assay to adjudicatemedRxiv : the preprint server for health sciences · 2023Article
- Effects of cohort, genotype, variant, and maternal β-blocker treatment on foetal heart rate predictors of inherited long QT syndrome.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2023Article
- Epilepsy-associated SCN2A (NaV1.2) variants exhibit diverse and complex functional properties.The Journal of general physiology · 2023Article
- Article
5 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
backgroundThe explosive growth in known human gene variation presents enormous challenges to current approaches for variant classification that have implications for diagnosis and treatment of many genetic diseases. For disorders caused by mutations in cardiac ion channels as in congenital arrhythmia syndromes, in vitro electrophysiological evidence has high value in discriminating pathogenic from benign variants, but these data are often lacking because assays are cost, time, and labor intensive.
methodsWe implemented a strategy for performing high-throughput functional evaluations of ion channel variants that repurposed an automated electrophysiological recording platform developed previously for drug discovery.
resultsWe demonstrated the success of this approach by evaluating 78 variants in KCNQ1, a major gene involved in genetic disorders of cardiac arrhythmia susceptibility. We benchmarked our results with traditional electrophysiological approaches and observed a high level of concordance. This strategy also enabled studies of dominant-negative behavior of variants exhibiting severe loss-of-function. Overall, our results provided functional data useful for reclassifying >65% of the studied KCNQ1 variants.
conclusionsOur results illustrate an efficient and high-throughput paradigm linking genotype to function for a human cardiac ion channel that will enable data-driven classification of large numbers of variants and create new opportunities for precision medicine.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.