CarDiag: Building of a Diagnostic/Prognostic Database for Human ERG Variant Effects
Study Details
Study Description
Brief Summary
Cardiac channelopathies induce severe heart rhythm or conduction disorders. Mutations of the KCNH2 gene, that encodes the human (h) ERG channel, is responsible for 30-40% of all cases of long QT syndrome (inherited LQT2). Besides, hERG is frequently responsible for off-target effects of several pharmacological agents (acquired LQT2). With the advent of Next Generation Sequencing, hundreds of new KCNH2 variants are accumulating in regional databases including those developed by french centers of references. Worldwide, we estimate there are more than 1000 variants for hERG channel. Unfortunately, many of these new variants appear to be of unknown functional significance in spite of available clinical and genetic information. Little is known on whether they affect the channel biophysical properties, its expression at the cell surface and/or its structure. Yet, this information is crucial to determine the real degree of pathogenicity of these variants, and therefore to make the proper diagnosis on inherited LQT2, counsel the patient for his treatment and improve the management of the patient's life. Our ambition is therefore to tackle this issue of variant significance by (i) launching a large-scale multi-functional evaluation of hERG variants, (ii) introducing for the first time a formatted large-scale pathogenicity annotation score for all variants that have been functionally evaluated by this multi-parametric approach, and (iii) regrouping all the relevant information collected in every French Regional centers of reference into a single National database hosted by an infrastructure that possesses enough flexibility for continuous data implementation and cross-referencing. The database will integrate the latest International guidelines for functional pathogenicity annotation. This project will also include the pharmacological characterization of several drugs susceptible to produce acquired LQT2 with variable severities. We aim to understand whether there are structural regions within hERG channel in which the introduction of a variant is more prone to increase the risk of acquired LQT2 or if, on the contrary, a set of variants may relatively protect some patients against LQT2-inducing drugs.
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Study Design
Outcome Measures
Primary Outcome Measures
- Multi-scale characterization of hERG variants [42 months]
Biophysical and pharmacological characterization; Trafficking impact of hERG variants; Structural impact of hERG variants using modeling tools
Secondary Outcome Measures
- Characterization of the effect of several drugs on KCNH2 variants [42 months]
Stratify KCNH2 gene variants according to their sensitivity to drugs known to induce acquired type 2 long QT syndrome
Eligibility Criteria
Criteria
Inclusion Criteria:
- Patients carrier of a mutation in KCNH2 gene
Exclusion Criteria:
- Patients who refuse to take part to research
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Nantes university hospital | Nantes | Loire-atlantique | France | 44093 |
| 2 | Hôpital Bichat - Claude Bernard | Paris | France | 75018 |
Sponsors and Collaborators
- Nantes University Hospital
- Institut National de la Santé Et de la Recherche Médicale, France
- Centre National de la Recherche Scientifique, France
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- RC21_0456