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

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.

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