Genome Sequencing Strategies for Genetics Diagnosis of Patients With Intellectual Disability (DEFIDIAG)
Primary Purpose
Intellectual Disability
Status
Active
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Trio Whole Genome Sequencing
Simplex Whole Genome Sequencing
Current French Reference strategy
Sponsored by
About this trial
This is an interventional diagnostic trial for Intellectual Disability focused on measuring Rare disease, Next generation sequencing genome, Diagnostic study, Medico-economic study
Eligibility Criteria
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:
- Between 0 and 5 years with stringent criteria (severe delayed development in terms of motor skills, language, and/or sociability) OR
- ≥ 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).
Inclusion criteria for biological parents
- Provision of signed and dated of both parents consent form.
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
Sites / Locations
- CHU d'Angers
- CHU Bordeaux
- Hospices Civil de Lyon
- CHU Dijon
- CHU de Grenoble-Alpes
- CHRU Lille
- Assistance publique - Hôpitaux de Marseille
- CHU Montpellier
- CHU Nantes
- Assistance publique - Hôpitaux de Paris - Groupe Hospitalier Pitié Salpétrière
- Assistance publique - Hôpitaux de Paris - Hôpital Necker - Enfants malades
- CHU Rennes
- CHU Rouen
- CHU Strasbourg
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
Mean cost of wavering diagnostic research
Estimation of the cost of wavering diagnostic research
Percentage of at least one modification in medical, medico-social, rehabilitative and psychological follow-up
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.
Median time and type of skills required for analyzing genetic data and for genetic confirmation
Median time to obtain results
Full Information
NCT ID
NCT04154891
First Posted
October 29, 2019
Last Updated
March 14, 2023
Sponsor
Institut National de la Santé Et de la Recherche Médicale, France
Collaborators
Commissariat A L'energie Atomique, Hospices Civils de Lyon, Centre Hospitalier Universitaire Dijon, University Hospital, Rouen, University Hospital, Strasbourg, APHP
1. Study Identification
Unique Protocol Identification Number
NCT04154891
Brief Title
Genome Sequencing Strategies for Genetics Diagnosis of Patients With Intellectual Disability
Acronym
DEFIDIAG
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
2. Study Status
Record Verification Date
March 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
March 13, 2020 (Actual)
Primary Completion Date
May 2023 (Anticipated)
Study Completion Date
May 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Institut National de la Santé Et de la Recherche Médicale, France
Collaborators
Commissariat A L'energie Atomique, Hospices Civils de Lyon, Centre Hospitalier Universitaire Dijon, University Hospital, Rouen, University Hospital, Strasbourg, APHP
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Intellectual Disability
Keywords
Rare disease, Next generation sequencing genome, Diagnostic study, Medico-economic study
7. Study Design
Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
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
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.
Allocation
N/A
Enrollment
3825 (Actual)
8. Arms, Groups, and Interventions
Intervention Type
Genetic
Intervention Name(s)
Trio Whole Genome Sequencing
Intervention Description
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.
Intervention Type
Genetic
Intervention Name(s)
Simplex Whole Genome Sequencing
Intervention Description
This analysis will be performed using only the index case following a similar strategy than the one used for the WGS trio
Intervention Type
Genetic
Intervention Name(s)
Current French Reference strategy
Intervention Description
Actual ANPGM recommendations defined by the following analysis: Fra-X + chromosomal microarray analysis + 44GPS
Primary Outcome Measure Information:
Title
Diagnostic Yield
Description
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.
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Causal structural change
Description
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.
Time Frame
12 months
Title
Incremental cost-effectiveness ratio
Description
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.
Time Frame
24 months
Title
Mean cost of wavering diagnostic research
Description
Estimation of the cost of wavering diagnostic research
Time Frame
24 months
Title
Percentage of at least one modification in medical, medico-social, rehabilitative and psychological follow-up
Time Frame
24 months
Title
Number and type of secondary data
Description
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.
Time Frame
12 months
Title
Median time and type of skills required for analyzing genetic data and for genetic confirmation
Time Frame
12 months
Title
Median time to obtain results
Time Frame
12 months
10. Eligibility
Sex
All
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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:
Between 0 and 5 years with stringent criteria (severe delayed development in terms of motor skills, language, and/or sociability) OR
≥ 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).
Inclusion criteria for biological parents
- Provision of signed and dated of both parents consent form.
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hélène DOLLFUS
Organizational Affiliation
Institut National de la Santé Et de la Recherche Médicale, France
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHU d'Angers
City
Angers
ZIP/Postal Code
49000
Country
France
Facility Name
CHU Bordeaux
City
Bordeaux
Country
France
Facility Name
Hospices Civil de Lyon
City
Bron
Country
France
Facility Name
CHU Dijon
City
Dijon
Country
France
Facility Name
CHU de Grenoble-Alpes
City
La Tronche
ZIP/Postal Code
38700
Country
France
Facility Name
CHRU Lille
City
Lille
Country
France
Facility Name
Assistance publique - Hôpitaux de Marseille
City
Marseille
Country
France
Facility Name
CHU Montpellier
City
Montpellier
Country
France
Facility Name
CHU Nantes
City
Nantes
Country
France
Facility Name
Assistance publique - Hôpitaux de Paris - Groupe Hospitalier Pitié Salpétrière
City
Paris
Country
France
Facility Name
Assistance publique - Hôpitaux de Paris - Hôpital Necker - Enfants malades
City
Paris
Country
France
Facility Name
CHU Rennes
City
Rennes
Country
France
Facility Name
CHU Rouen
City
Rouen
Country
France
Facility Name
CHU Strasbourg
City
Strasbourg
Country
France
12. IPD Sharing Statement
Citations:
PubMed Identifier
35178068
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.
Results Reference
background
PubMed Identifier
35444683
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.
Results Reference
background
PubMed Identifier
35499524
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.
Results Reference
background
PubMed Identifier
36846113
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.
Results Reference
background
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Genome Sequencing Strategies for Genetics Diagnosis of Patients With Intellectual Disability
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