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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Intellectual Disability
• Intervention / Treatment: Genetic: Trio Whole Genome Sequencing; Genetic: Simplex Whole Genome Sequencing; Genetic: Current French Reference strategy

• Study Type: Interventional
• Enrollment (Actual): 3825
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Angers, France, 49000
    • CHU d'Angers
  • Bordeaux, France
    • CHU Bordeaux
  • Bron, France
    • Hospices Civil de Lyon
  • Dijon, France
    • CHU Dijon
  • La Tronche, France, 38700
    • CHU de Grenoble-Alpes
  • Lille, France
    • CHRU Lille
  • Marseille, France
    • Assistance Publique - Hopitaux de Marseille
  • Montpellier, France
    • CHU Montpellier
  • Nantes, France
    • CHU Nantes
  • Paris, France
    • Assistance publique - Hôpitaux de Paris - Groupe Hospitalier Pitié Salpétrière
  • Paris, France
    • Assistance publique - Hôpitaux de Paris - Hôpital Necker - Enfants malades
  • Rennes, France
    • CHU Rennes
  • Rouen, France
    • CHU Rouen
  • Strasbourg, France
    • CHU Strasbourg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: Single

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	24 months
Mean cost of wavering diagnostic research	Estimation of the cost of wavering diagnostic research	24 months
Percentage of at least one modification in medical, medico-social, rehabilitative and psychological follow-up		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.	12 months
Median time and type of skills required for analyzing genetic data and for genetic confirmation		12 months
Median time to obtain results		12 months

Collaborators and Investigators

• Sponsor: Institut National de la Santé Et de la Recherche Médicale, France
• Collaborators: Hospices Civils de Lyon; University Hospital, Rouen; Centre Hospitalier Universitaire Dijon; APHP; Commissariat A L'energie Atomique; University Hospital, Strasbourg
• Investigators: Principal Investigator: Hélène DOLLFUS, Institut National de la Santé Et de la Recherche Médicale, France

Publications and helpful links

General Publications

• Lejeune C, Robert-Viard C, Meunier-Beillard N, Borel MA, Gourves L, Staraci S, Soilly AL, Guillemin F, Seror V, Achit H, Bouctot M, Asensio ML, Briffaut AS, Delmas C, Bruel AL, Benoit A, Simon A, Gerard B, Hadj Abdallah H, Lyonnet S, Faivre L, Thauvin-Robinet C, Odent S, Heron D, Sanlaville D, Frebourg T, Muller J, Duffourd Y, Boland A, Deleuze JF, Esperou H, Binquet C, Dollfus H. The Economic, Medical and Psychosocial Consequences of Whole Genome Sequencing for the Genetic Diagnosis of Patients With Intellectual Disability: The DEFIDIAG Study Protocol. Front Genet. 2022 Apr 4;13:852472. doi: 10.3389/fgene.2022.852472. eCollection 2022.
• Binquet C, Lejeune C, Faivre L, Bouctot M, Asensio ML, Simon A, Deleuze JF, Boland A, Guillemin F, Seror V, Delmas C, Esperou H, Duffourd Y, Lyonnet S, Odent S, Heron D, Sanlaville D, Frebourg T, Gerard B, Dollfus H. Genome Sequencing for Genetics Diagnosis of Patients With Intellectual Disability: The DEFIDIAG Study. Front Genet. 2022 Feb 1;12:766964. doi: 10.3389/fgene.2021.766964. eCollection 2021.
• Meuwissen M, Verstraeten A, Ranza E, Iwaszkiewicz J, Bastiaansen M, Mateiu L, Nemegeer M, Meester JAN, Afenjar A, Amaral M, Ballhausen D, Barnett S, Barth M, Asselbergh B, Spaas K, Heeman B, Bassetti J, Blackburn P, Schaer M, Blanc X, Zoete V, Casas K, Courtin T, Doummar D, Guerry F, Keren B, Pappas J, Rabin R, Begtrup A, Shinawi M, Vulto-van Silfhout AT, Kleefstra T, Wagner M, Ziegler A, Schaefer E, Gerard B, De Bie CI, Holwerda SJB, Abbot MA, Antonarakis SE, Loeys B. Heterozygous variants in CTR9, which encodes a major component of the PAF1 complex, are associated with a neurodevelopmental disorder. Genet Med. 2022 Jul;24(7):1583-1591. doi: 10.1016/j.gim.2022.04.003. Epub 2022 May 2.
• Ravindran E, Lesca G, Januel L, Goldgruber L, Dickmanns A, Margot H, Kaindl AM. Case report: Compound heterozygous NUP85 variants cause autosomal recessive primary microcephaly. Front Neurol. 2023 Feb 9;14:1124886. doi: 10.3389/fneur.2023.1124886. eCollection 2023.

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2020
• Primary Completion (Actual): December 31, 2023
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: October 29, 2019
• First Submitted That Met QC Criteria: November 4, 2019
• First Posted (Actual): November 7, 2019

Study Record Updates

• Last Update Posted (Estimated): March 5, 2024
• Last Update Submitted That Met QC Criteria: March 4, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Rare disease; Next generation sequencing genome; Diagnostic study; Medico-economic study
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurodevelopmental Disorders; Intellectual Disability
• Other Study ID Numbers: C16-110; 2018-A00680-55 (Other Identifier: IDRCB)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No