Clinical trial NCT04154891: Genome Sequencing Strategies for Genetics Diagnosis of Patients With Intellectual Disability
Official title: Etude Pilote Des différentes stratégies de séquençage Haut débit du génome Pour le Diagnostic génétique Des Patients Atteints de déficience Intellectuelle
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Intellectual Disability
Keywords: Rare disease
Next generation sequencing genome
Diagnostic study
Medico-economic study
Lead sponsor: Institut National de la Santé Et de la Recherche Médicale, France
Sponsor class: OTHER_GOV
Collaborators: name: Commissariat A L'energie Atomique
name: Hospices Civils de Lyon
name: Centre Hospitalier Universitaire Dijon
name: University Hospital, Rouen
name: University Hospital, Strasbourg
name: APHP
First posted: 2019-11-07
Enrollment: 3825
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
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.
Primary purpose: DIAGNOSTIC

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.


Eligibility 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

Primary outcomes:
measure: Diagnostic Yield
timeFrame: 12 months
Secondary outcomes:
measure: Causal structural change
timeFrame: 12 months
measure: Incremental cost-effectiveness ratio
timeFrame: 24 months
measure: Mean cost of wavering diagnostic research
timeFrame: 24 months
measure: Percentage of at least one modification in medical, medico-social, rehabilitative and psychological follow-up
timeFrame: 24 months
measure: Number and type of secondary data
timeFrame: 12 months
measure: Median time and type of skills required for analyzing genetic data and for genetic confirmation
timeFrame: 12 months
measure: Median time to obtain results
timeFrame: 12 months
Other outcomes:
Locations:
city: Angers
country: France
facility: CHU d'Angers
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Bron
country: France
facility: Hospices Civil de Lyon
city: Dijon
country: France
facility: CHU Dijon
city: La Tronche
country: France
facility: CHU de Grenoble-Alpes
city: Lille
country: France
facility: CHRU Lille
city: Marseille
country: France
facility: Assistance publique - Hôpitaux de Marseille
city: Montpellier
country: France
facility: CHU Montpellier
city: Nantes
country: France
facility: CHU Nantes
city: Paris
country: France
facility: Assistance publique - Hôpitaux de Paris - Groupe Hospitalier Pitié Salpétrière
city: Paris
country: France
facility: Assistance publique - Hôpitaux de Paris - Hôpital Necker - Enfants malades
city: Rennes
country: France
facility: CHU Rennes
city: Rouen
country: France
facility: CHU Rouen
city: Strasbourg
country: France
facility: CHU Strasbourg
Study officials:
affiliation: Institut National de la Santé Et de la Recherche Médicale, France
name: Hélène DOLLFUS
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.