ArticleClinical and translational medicine2021
A standardised hERG phenotyping pipeline to evaluate KCNH2 genetic variant pathogenicity.
Article in Clinical and translational medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 12 citations in OpenAlex.
- Quantitative analysis of trafficking defects induced by heterozygous expression of hERG voltage sensor domain variants.Channels (Austin, Tex.) · 2026Article
- Personalized in vitro models reveal functional impact of aHeart rhythm O2 · 2026Article
- SPARC: a structural pathogenicity algorithm for risk classification of hERG variants.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 · 2026Article
- High-Throughput Methods for Variant Functional Assessment in Cardiac Disease.Circulation. Genomic and precision medicine · 2026Review
- Computational insights into the mechanisms underlying structural destabilization and recovery in trafficking-deficient hERG mutants.Frontiers in molecular biosciences · 2024Article
- Predicting hERG repolarization power at 37°C from recordings at room temperature.Clinical and translational medicine · 2023Article
- A need for exhaustive and standardized characterization of ion channels activity. The case of KFrontiers in physiology · 2023Review
- Mutation-Specific Differences in Kv7.1 (International journal of molecular sciences · 2022Review
- Evolutionary coupling analysis guides identification of mistrafficking-sensitive variants in cardiac KFrontiers in pharmacology · 2022Article
- A standardised hERG phenotyping pipeline to evaluate KCNH2 genetic variant pathogenicity.Clinical and translational medicine · 2021Article
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17 authors at 3 institutions in 1 country.
Funding
Abstract
BACKGROUND AND
aimsMutations in KCNH2 cause long or short QT syndromes (LQTS or SQTS) predisposing to life-threatening arrhythmias. Over 1000 hERG variants have been described by clinicians, but most remain to be characterised. The objective is to standardise and accelerate the phenotyping process to contribute to clinician diagnosis and patient counselling. In silico evaluation was also included to characterise the structural impact of the variants.
methodsWe selected 11 variants from known LQTS patients and two variants for which diagnosis was problematic. Using the Gibson assembly strategy, we efficiently introduced mutations in hERG cDNA despite GC-rich sequences. A pH-sensitive fluorescent tag was fused to hERG for efficient evaluation of channel trafficking. An optimised 35-s patch-clamp protocol was developed to evaluate hERG channel activity in transfected cells. R software was used to speed up analyses.
resultsIn the present work, we observed a good correlation between cell surface expression, assessed by the pH-sensitive tag, and current densities. Also, we showed that the new biophysical protocol allows a significant gain of time in recording ion channel properties and provides extensive information on WT and variant channel biophysical parameters, that can all be recapitulated in a single parameter defined herein as the repolarisation power. The impacts of the variants on channel structure were also reported where structural information was available. These three readouts (trafficking, repolarisation power and structural impact) define three pathogenicity indexes that may help clinical diagnosis.
conclusionsFast-track characterisation of KCNH2 genetic variants shows its relevance to discriminate mutants that affect hERG channel activity from variants with undetectable effects. It also helped the diagnosis of two new variants. This information is meant to fill a patient database, as a basis for personalised medicine. The next steps will be to further accelerate the process using an automated patch-clamp system.
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