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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Long QT Syndrome

• Study Type: Observational
• Enrollment (Estimated): 600

Contacts and Locations

• Study Contact: Name: Vincent Probst, PUPH; Phone Number: 0240165279; Email: vincent.probst@chu-nantes.fr

Study Locations

• France
  • Paris, France, 75018
    • Recruiting
    • Hôpital Bichat - Claude Bernard
    • Contact: Isabelle Denjoy, Dr
  • Loire-atlantique
    • Nantes, Loire-atlantique, France, 44093
      • Recruiting
      • Nantes University Hospital
      • Contact: Vincent Probst, PUPH; Phone Number: +33240165279; Email: vincent.probst@chu-nantes.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

A collective effort will be conducted by all partners on identifying sets of priorities for KCNH2 variants. Priority 1 will be all the variants for which clinical and genetic data cannot decide on their own about the pathogenicity. All French variants will be included in this group. It may be enlarged by interesting variants identified from Clinvar. Priority 2 variants will be those for which pathogenicity is established but for which additional functional, pharmacological and structural data may be of interest. Special mention will be attributed to the variants that localize on hERG regions well defined structurally. Priority 3 are all other variants.

Description

Inclusion Criteria:

• Patients carrier of a mutation in KCNH2 gene

Exclusion Criteria:

• Patients who refuse to take part to research

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Nantes University Hospital
• Collaborators: Institut National de la Santé Et de la Recherche Médicale, France; Centre National de la Recherche Scientifique, France

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2021
• Primary Completion (Actual): December 31, 2023
• Study Completion (Estimated): March 24, 2026

Study Registration Dates

• First Submitted: October 12, 2023
• First Submitted That Met QC Criteria: October 12, 2023
• First Posted (Actual): October 17, 2023

Study Record Updates

• Last Update Posted (Actual): May 23, 2025
• Last Update Submitted That Met QC Criteria: May 22, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Long QT syndrome; KCNH2 gene variants
• Additional Relevant MeSH Terms: Cardiac Conduction System Disease; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Arrhythmias, Cardiac; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Defects, Congenital; Long QT Syndrome
• Other Study ID Numbers: RC21_0456

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Implementation of a new web-accessible variant-centric database

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No