ArticleAmerican journal of human genetics2022
A massively parallel assay accurately discriminates between functionally normal and abnormal variants in a hotspot domain of KCNH2.
Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 30 citations in OpenAlex.
- Functional characterization and allele-specific RNA interference-based rescue of KCNH2 p.F68C variant associated with long QT syndrome.Molecular genetics and genomics : MGG · 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
- Article
- Leaving no patient behind! Expert recommendation in the use of innovative technologies for diagnosing rare diseases.Orphanet journal of rare diseases · 2024Review
- Multisite Validation of a Functional Assay to AdjudicateCirculation. Genomic and precision medicine · 2024Article
- Multiplexed Assays of Variant Effect and Automated Patch-clamping ImprovemedRxiv : the preprint server for health sciences · 2024Article
- High-throughput functional mapping of variants in an arrhythmia gene, KCNE1, reveals novel biology.Genome medicine · 2024Article
- Very important pharmacogenetic variants landscape and potential clinical relevance in the Zhuang population from Yunnan province.Scientific reports · 2024Article
- Multi-site validation of a functional assay to adjudicatemedRxiv : the preprint server for health sciences · 2023Article
- Deep mutational scanning of proteins in mammalian cells.Cell reports methods · 2023Review
- Article
- Scanning mutagenesis of the voltage-gated sodium channel NaCell reports · 2023Article
- Continuous Bayesian variant interpretation accounts for incomplete penetrance among Mendelian cardiac channelopathies.Genetics in medicine : official journal of the American College of Medical Genetics · 2023Article
- Development of automated patch clamp assays to overcome the burden of variants of uncertain significance in inheritable arrhythmia syndromes.Frontiers in physiology · 2023Review
- Coupling the Cardiac Voltage-Gated Sodium Channel to Channelrhodopsin-2 Generates Novel Optical Switches for Action Potential Studies.Membranes · 2022Article
- A calibrated functional patch-clamp assay to enhance clinical variant interpretation in KCNH2-related long QT syndrome.American journal of human genetics · 2022Article
- Evolutionary coupling analysis guides identification of mistrafficking-sensitive variants in cardiac KFrontiers in pharmacology · 2022Article
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
Many genes, including KCNH2, contain "hotspot" domains associated with a high density of variants associated with disease. This has led to the suggestion that variant location can be used as evidence supporting classification of clinical variants. However, it is not known what proportion of all potential variants in hotspot domains cause loss of function. Here, we have used a massively parallel trafficking assay to characterize all single-nucleotide variants in exon 2 of KCNH2, a known hotspot for variants that cause long QT syndrome type 2 and an increased risk of sudden cardiac death. Forty-two percent of KCNH2 exon 2 variants caused at least 50% reduction in protein trafficking, and 65% of these trafficking-defective variants exerted a dominant-negative effect when co-expressed with a WT KCNH2 allele as assessed using a calibrated patch-clamp electrophysiology assay. The massively parallel trafficking assay was more accurate (AUC of 0.94) than bioinformatic prediction tools (REVEL and CardioBoost, AUC of 0.81) in discriminating between functionally normal and abnormal variants. Interestingly, over half of variants in exon 2 were found to be functionally normal, suggesting a nuanced interpretation of variants in this "hotspot" domain is necessary. Our massively parallel trafficking assay can provide this information prospectively.
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