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Genome Sequencing Strategies for Genetics Diagnosis of Patients With Intellectual Disability (DEFIDIAG)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04154891
Recruitment Status : Recruiting
First Posted : November 7, 2019
Last Update Posted : June 11, 2020
Commissariat à l'énergie atomique et aux énergies alternatives
Hospices Civils de Lyon
Centre Hospitalier Universitaire Dijon
University Hospital, Rouen
University Hospital, Strasbourg
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Intellectual Disability Genetic: Trio Whole Genome Sequencing Genetic: Simplex Whole Genome Sequencing Genetic: Current French Reference strategy Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 3825 participants
Allocation: N/A
Intervention Model: Single Group Assignment
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.
Masking: Single (Outcomes Assessor)
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.
Primary Purpose: Diagnostic
Official Title: Etude Pilote Des différentes stratégies de séquençage Haut débit du génome Pour le Diagnostic génétique Des Patients Atteints de déficience Intellectuelle
Actual Study Start Date : March 13, 2020
Estimated Primary Completion Date : March 2022
Estimated Study Completion Date : March 2023

Resource links provided by the National Library of Medicine

Intervention Details:
  • 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

Primary Outcome Measures :
  1. Diagnostic Yield [ Time Frame: 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 :
  1. Causal structural change [ Time Frame: 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.

  2. Incremental cost-effectiveness ratio [ Time Frame: 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.

  3. Mean cost of wavering diagnostic research [ Time Frame: 24 months ]
    Estimation of the cost of wavering diagnostic research

  4. Percentage of at least one modification in medical, medico-social, rehabilitative and psychological follow-up [ Time Frame: 24 months ]
  5. Number and type of secondary data [ Time Frame: 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.

  6. Median time and type of skills required for analyzing genetic data and for genetic confirmation [ Time Frame: 12 months ]
  7. Median time to obtain results [ Time Frame: 12 months ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
  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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04154891

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Contact: Hélène ESPEROU +33 1 44 23 67 00

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CHU Bordeaux Recruiting
Bordeaux, France
Contact: Didier LACOMBE         
Hospices Civil de Lyon Recruiting
Bron, France
Contact: Patrick EDERY         
CHU Dijon Recruiting
Dijon, France
Contact: Laurence FAIVRE         
CHRU Lille Recruiting
Lille, France
Contact: Roseline CAUMES         
Assistance publique - Hôpitaux de Marseille Recruiting
Marseille, France
Contact: Nicole PHILIP         
CHU Montpellier Recruiting
Montpellier, France
Contact: David GENEVIEVE         
CHU Nantes Recruiting
Nantes, France
Contact: Bertrand ISIDOR         
Assistance publique - Hôpitaux de Paris - Groupe Hospitalier Pitié Salpétrière Recruiting
Paris, France
Contact: Delphine HERON         
Assistance publique - Hôpitaux de Paris - Hôpital Necker - Enfants malades Recruiting
Paris, France
Contact: Stanislas LYONNET         
CHU Rennes Recruiting
Rennes, France
Contact: Sylvie ODENT         
CHU Rouen Recruiting
Rouen, France
Contact: Gael NICOLAS         
CHU Strasbourg Recruiting
Strasbourg, France
Contact: Helene DOLLFUS         
Sponsors and Collaborators
Institut National de la Santé Et de la Recherche Médicale, France
Commissariat à l'énergie atomique et aux énergies alternatives
Hospices Civils de Lyon
Centre Hospitalier Universitaire Dijon
University Hospital, Rouen
University Hospital, Strasbourg
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Principal Investigator: Hélène DOLLFUS Institut National de la Santé Et de la Recherche Médicale, France
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Responsible Party: Institut National de la Santé Et de la Recherche Médicale, France Identifier: NCT04154891    
Other Study ID Numbers: C16-110
2018-A00680-55 ( Other Identifier: IDRCB )
First Posted: November 7, 2019    Key Record Dates
Last Update Posted: June 11, 2020
Last Verified: November 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Institut National de la Santé Et de la Recherche Médicale, France:
Rare disease
Next generation sequencing genome
Diagnostic study
Medico-economic study
Additional relevant MeSH terms:
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Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Neurodevelopmental Disorders
Mental Disorders