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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
DIAGNOSTIC
Masking
SINGLE
Enrollment
3,825
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.
This analysis will be performed using only the index case following a similar strategy than the one used for the WGS trio
Actual ANPGM recommendations defined by the following analysis: Fra-X + chromosomal microarray analysis + 44GPS
CHU d'Angers
Angers, France
CHU Bordeaux
Bordeaux, France
Hospices Civil de Lyon
Bron, France
CHU Dijon
Dijon, France
CHU de Grenoble-Alpes
La Tronche, France
CHRU Lille
Lille, France
Assistance publique - Hôpitaux de Marseille
Marseille, France
CHU Montpellier
Montpellier, France
CHU Nantes
Nantes, France
Assistance publique - Hôpitaux de Paris - Groupe Hospitalier Pitié Salpétrière
Paris, France
...and 4 more locations
Diagnostic Yield
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.
Time frame: 12 months
Causal structural change
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.
Time frame: 12 months
Incremental cost-effectiveness ratio
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.
Time frame: 24 months
Mean cost of wavering diagnostic research
Estimation of the cost of wavering diagnostic research
Time frame: 24 months
Percentage of at least one modification in medical, medico-social, rehabilitative and psychological follow-up
Time frame: 24 months
Number and type of secondary data
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.
Time frame: 12 months
Median time and type of skills required for analyzing genetic data and for genetic confirmation
Time frame: 12 months
Median time to obtain results
Time frame: 12 months
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