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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

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

undefined - undefined (Child, Adult, Older Adult)All SexesAccepts Healthy Volunteers

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).
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

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

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

Time Frame

12 months

Secondary Outcome Measure Information:

Title

Causal structural change

Description

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

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

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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