Building of a Diagnostic/Prognostic Database for Human ERG Variant Effects

Long QT Syndrome Clinical Trial

— CarDiag  

Official title:

Building of a Diagnostic/Prognostic Database by High-throughput Multiplexed Assays for Human ERG Variant Effects

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06087367
• Other study ID #: RC21_0456
• Status: Recruiting
• Start date: September 20, 2021
• Est. completion date: March 24, 2025

Study information

• Verified date: October 2023
• Source: Nantes University Hospital
• Contact: Vincent Probst, PUPH
• Phone: 0240165279
• Email: vincent.probst[@]chu-nantes.fr
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 600
• Est. completion date: March 24, 2025
• Est. primary completion date: March 24, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Patients carrier of a mutation in KCNH2 gene

Exclusion Criteria:

• Patients who refuse to take part to research

Related Conditions & MeSH terms

• Long QT Syndrome

Locations

Country	Name	City	State
France	Nantes university hospital	Nantes	Loire-atlantique
France	Hôpital Bichat - Claude Bernard	Paris

Sponsors (3)

Lead Sponsor	Collaborator
Nantes University Hospital	Centre National de la Recherche Scientifique, France, Institut National de la Santé Et de la Recherche Médicale, France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To develop a database listing KCNH2 variants and their clinical impact	Biophysical and pharmacological characterization; Trafficking impact of hERG variants; Structural impact of hERG variants using modeling tools	42 months
Secondary	To stratify KCNH2 gene variants according to their sensitivity to drugs	Stratify KCNH2 gene variants according to their sensitivity to drugs known to induce acquired type 2 long QT syndrome	42 months