Genome Sequencing Strategies for Genetics Diagnosis of Patients With Intellectual Disability

Conditions

Intellectual Disability

Keywords

Rare disease, Next generation sequencing genome, Diagnostic study, Medico-economic study

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.

El Chehadeh S, Heide S, Quélin C, Rio M, Margot H, Geneviève D, Isidor B, Goldenberg A, Guégan C, Lesca G, Willems M, Ormières C, Caumes R, Busa T, Bonneau D, Guerrot AM, Marey I, Vera G, Marzin P, Philippe A, Garde A, Coubes C, Vincent M, Michaud V, Mignot C, Charles P, Sigaudy S, Edery P, Lacombe D, Boland A, Nowak F, Bouctot M, Humbert-Asensio ML, Simon A, Chennen K, Sabour N, Delmas C, Nicolas G, Saugier-Veber P, Lecoquierre F, Cassinari K, Keren B, Courtin T, De Sainte Agathe JM, Malan V, Barcia G, Tran Mau-Them F, Safraou H, Philippe C, Thévenon J, Chatron N, Januel L, Piton A, Haushalter V, Gérard B, Lejeune C, Faivre L, Sanlaville D, Héron D, Odent S, Nitschké P, Schluth-Bolard C, Lyonnet S, Deleuze JF, Binquet C, Dollfus H, DEFIDIAG study group.

2025-10-03

10.1186/s13073-025-01527-4

P59 - Coût de l'analyse du génome chez les patients atteints de déficience intellectuelle : une étude de micro-costing dans un contexte français

C. Robert-Viard, Anne Boland, B. Gérard, Serge Romana, Patrick Nitschké et al. (8 authors)

Journal of Epidemiology and Population Health2024-05-01

10.1016/j.jeph.2024.202499

The Economic, Medical and Psychosocial Consequences of Whole Genome Sequencing for the Genetic Diagnosis of Patients With Intellectual Disability: The DEFIDIAG Study Protocol

Catherine Lejeune, C. Robert-Viard, Nicolas Meunier‐Beillard, Myriam Alice Borel, Léna Gourvès et al. (33 authors)

Frontiers in Genetics2022-04-043 citations

10.3389/fgene.2022.852472

Genome Sequencing for Genetics Diagnosis of Patients With Intellectual Disability: The DEFIDIAG Study.

Binquet C, Lejeune C, Faivre L, Bouctot M, Asensio ML, Simon A, Deleuze JF, Boland A, Guillemin F, Seror V, Delmas C, Espérou H, Duffourd Y, Lyonnet S, Odent S, Heron D, Sanlaville D, Frebourg T, Gerard B, Dollfus H.

2022-02-018 citations

10.3389/fgene.2021.766964

Interventions

GENETICWhole Genome Sequencing

The 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.

Study design

Allocation

NA

Intervention model

SINGLE_GROUP

Primary purpose

DIAGNOSTIC

Masking

NONE

Masking description

The results of the different strategies will be interpreted blindly, each participating laboratory being in charge for a given investigation center, either of 1) the trio or 2) the 44GPS (part of the reference strategy) and, for the randomized sub-population of the overall population coming for a first genetic advice, simplex analyses. Fra-X and chromosomal microarray analysis corresponding to the reference strategy will follow the routine circuit, which is mainly independent from the WGS circuit.

Intervention model description

Prospective multicenter diagnostic study comparing the percentage of Intellectual Deficiency (ID) causal diagnosis obtained using 2 main different strategies (Whole Genome Sequencing using a trio strategy (WGST), and reference strategy) applied blindly to consecutive patients with no obvious diagnosis. Each included patient will be his own control; he will benefit from the two main strategies compared, in parallel. The diagnostic yield of Whole Genome Sequencing using a simplex strategy (WGSs) will be also investigated in parallel to the two main strategies but only in a randomized subgroup of the overall population coming for a first genetic advice.

Eligibility

Sex/Gender

ALL

Healthy volunteers

Yes

Inclusion criteria

1. Inclusion criteria for children or adults with ID of unknown etiology (index case) In order to be eligible to participate in this study, an individual must meet all the following criteria: * Age: 1. Between 0 and 5 years with stringent criteria (severe delayed development in terms of motor skills, language, and/or sociability) OR 2. ≥ 6 years: patients with ID, whatever the severity (but with proven ID by ad hoc neuropsychological testing) and the associated manifestations * Without any obvious diagnosis identified during a genetic consultation in one of the participating center (i.e., an obvious syndrome with ID with well-known molecular diagnosis is excluded); * Provision of signed and dated of "participant" consent form; * Stated willingness to comply with all study procedures and availability for the duration of the study. Patient with a social security in compliance with the French law (Provisions relating to research involving the human person provided for in Articles L 1121-1 et seq. of the French Public Health Code). 2. Inclusion criteria for biological parents \- Provision of signed and dated of both parents consent form. 3. Non-inclusion criteria * An individual, who presents any condition which in the investigator's opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol, will not be eligible; * Patients with isolated learning disabilities; * One or both parents with ID; * Parent placed under judicial protection (tutelle, curatelle et sauvegarde de justice) ; * Patient with a known etiological diagnosis (non-genetic, previously proven Fra-X syndrome, know chromosomal anomaly, known pathogenic or probably pathogenic variant identified in an ID gene by any technique). * For patient concerning by biobank project: hypersensitivity to local anesthesia

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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.
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.
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	—
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.
Median time and type of skills required for analyzing genetic data and for genetic confirmation	12 months	—
Median time to obtain results	12 months	—

Countries

France

Contacts

PRINCIPAL_INVESTIGATORHélène DOLLFUS

Institut National de la Santé Et de la Recherche Médicale, France

Outcome results

None listed