NCT04154891

Genome Sequencing Strategies for Genetics Diagnosis of Patients With Intellectual Disability

Etude Pilote Des différentes stratégies de séquençage Haut débit du génome Pour le Diagnostic génétique Des Patients Atteints de déficience Intellectuelle

• Status: Completed
• Phase: N/A
• Study type: Interventional
• Enrollment: 3,825 (actual)
• Sponsor: Institut National de la Santé Et de la Recherche Médicale, France · Other Government
• Sex: All
• Age: —
• Healthy volunteers: Accepted

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.

Conditions

• Intellectual Disability

Interventions

Type	Name	Description
GENETIC	Trio Whole Genome Sequencing	WGS trio analysis will be performed using the genome data of the index case in addition to the genome data of his parents. This analysis will follow a consensus protocol that contains 3 obligatory steps: first of all, de novo variants (SNV, CNV and others SV) will be examined in the whole genome data set; then, a SNV/CNV/other SV analysis will be performed under a AR or X linked Mendelian mode hypothesis in the whole genomic regions of a OMIM extended list (that contains all genes already involved in human genetic diseases). Finally, analysis will focus on inherited pathogenic variants under an AD mode hypothesis (analysis of variations already reported as pathogenic in clinVar or HGMD pro; CNV or truncating variation in OMIM genes, etc). When these 3 steps analysis is completed then variants of interest identified at each step will be recorded until examination by a specific multidisciplinary meeting.
GENETIC	Simplex Whole Genome Sequencing	This analysis will be performed using only the index case following a similar strategy than the one used for the WGS trio
GENETIC	Current French Reference strategy	Actual ANPGM recommendations defined by the following analysis: Fra-X + chromosomal microarray analysis + 44GPS

Timeline

• Start date: 2020-03-13
• Primary completion: 2023-12-31
• Completion: 2025-06-16
• First posted: 2019-11-07
• Last updated: 2025-09-11

Locations

14 sites across 1 country: France