Genome Sequencing Strategies for Genetics Diagnosis of Patients With Intellectual Disability

Not Applicable

Active, not recruiting

• Conditions: Intellectual Disability

• Registration Number: NCT04154891
• Lead Sponsor: Institut National de la Santé Et de la Recherche Médicale, France

Brief Summary

Introduction : Intellectual Disability (ID) is the most common cause of referral in the pediatric genetic centers and is characterized by an extreme genetic heterogeneity corresponding to a myriad of rare diseases that complicates the identification of ID's.

Overall today in France, for non-syndromic ID affected patients, the Fra-X detection, the chromosomal microarray analysis and Gene Panel Strategy of 44 ID selected genes leads to a global diagnostic yield for 1/3 patients leaving 2/3 of patients still with no diagnosis.

The advent, and burst, of Next Generation Sequencing (NGS) technologies has clearly revolutionized the approaches to diagnosis and research in the field of rare diseases at an international. That's why the main hypothesis of DEFIDIAG is that Whole Genome Sequencing (WGS) could allow to improve the diagnostic performance and cost-effectiveness for French patients with ID.

Objective : The main objective of this study is to compare ther percentage of genetic causal diagnosis identified in ID patients by performing trio WGS analysis vs the use of the current French reference strategy (ACPA, X-Fra, DI 44).

Methods and design : This is a prospective study. The investigators expect to include 1275 index case with his/her 2 biological unaffected parents.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-10-29
• Study First Submitted QC: 2019-11-04
• Study First Posted: 2019-11-07
• Study Start: 2020-03-13
• Primary Completion: 2023-12-31
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-15
• Last Update Posted: 2025-01-16
• Study Completion: 2025-06-19

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 3825

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Primary Outcome Measures

Name	Time	Method
Diagnostic Yield	12 months	The primary study endpoint is the identification of a causal diagnosis of ID defined as the identification of one class 4 or 5 variant (or two in case of autosomal recessive inheritance) that explains the symptoms presented by the patient. In addition variants classified as 3+, anticipated to become future 4 will be recorded. Specific analysis and follow up of the variant classified as 3+ (i.e. with a high probability of pathogenicity) will be done after the end of the protocol to determine the class 3+ to class 4-5 switch proportion and to describe the new genes/mechanisms involved in ID and revealed by DEFIDIAG.

Secondary Outcome Measures

Name	Time	Method
Median time and type of skills required for analyzing genetic data and for genetic confirmation	12 months
Incremental cost-effectiveness ratio	24 months	The cost-effectiveness endpoint will be an efficiency criterion based on the estimation of an incremental cost-effectiveness ratio, expressed in terms of cost per additional positive diagnosis.
Number and type of secondary data	12 months	The number and type of SFs (class 4 or 5 mutation(s)) identified in the parents that specifically consent to this study will be recorded in a specific report. The outcome will be defined by the percentage of SFs in the studied population and the number and type of medical consequences following their identification.
Causal structural change	12 months	Identification of causal structural changes (CNV, translocation, inversion) in the first investigation population (confirmed during the MDM for the WGS strategies); The clinical characteristics of patients and the diagnostic yield at each step of the incremental selection within WGS analyses (44GPS, OMIMOME, WES, WGS) according to the results of the preceding step as well as according to the results of chromosomal microarray analysis and 44GPS will also be parameters of interest in the whole population.
Mean cost of wavering diagnostic research	24 months	Estimation of the cost of wavering diagnostic research
Percentage of at least one modification in medical, medico-social, rehabilitative and psychological follow-up	24 months
Median time to obtain results	12 months

Trial Locations

Locations (14)

CHU Bordeaux; 🇫🇷 Bordeaux, France

Assistance publique - Hôpitaux de Marseille; 🇫🇷 Marseille, France

CHU Nantes; 🇫🇷 Nantes, France

CHU Strasbourg; 🇫🇷 Strasbourg, France

CHU Rennes; 🇫🇷 Rennes, France

CHU Rouen; 🇫🇷 Rouen, France

CHU d'Angers; 🇫🇷 Angers, France

CHU Montpellier; 🇫🇷 Montpellier, France

Assistance publique - Hôpitaux de Paris - Hôpital Necker - Enfants malades; 🇫🇷 Paris, France

CHU Dijon; 🇫🇷 Dijon, France

CHU de Grenoble-Alpes; 🇫🇷 La Tronche, France

Hospices Civil de Lyon; 🇫🇷 Bron, France

CHRU Lille; 🇫🇷 Lille, France

Assistance publique - Hôpitaux de Paris - Groupe Hospitalier Pitié Salpétrière; 🇫🇷 Paris, France