Genome Sequencing Strategies for Genetics Diagnosis of Patients With Intellectual Disability

NCT ID: NCT04154891

Last Updated: 2025-09-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 3825 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-03-13
• Study Completion Date: 2025-06-16

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.

Conditions

Intellectual Disability

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: SINGLE

Interventions

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.

Intervention Type: 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

Intervention Type: GENETIC

Current French Reference strategy

Actual ANPGM recommendations defined by the following analysis: Fra-X + chromosomal microarray analysis + 44GPS

Intervention Type: GENETIC

Eligibility Criteria

Inclusion Criteria

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).

• Provision of signed and dated of both parents consent form.

• 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

• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Commissariat A L'energie Atomique

OTHER_GOV

Sponsor Role: collaborator

Hospices Civils de Lyon

OTHER

Sponsor Role: collaborator

Centre Hospitalier Universitaire Dijon

OTHER

Sponsor Role: collaborator

University Hospital, Rouen

OTHER

Sponsor Role: collaborator

University Hospital, Strasbourg

OTHER

Sponsor Role: collaborator

APHP

OTHER

Sponsor Role: collaborator

Institut National de la Santé Et de la Recherche Médicale, France

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Hélène DOLLFUS

Role: PRINCIPAL_INVESTIGATOR

Institut National de la Santé Et de la Recherche Médicale, France

Locations

CHU d'Angers

Angers, , France

CHU Bordeaux

Bordeaux, , France

Hospices Civil de Lyon

Bron, , France

CHU Dijon

Dijon, , France

CHU de Grenoble-Alpes

La Tronche, , France

CHRU Lille

Lille, , France

Assistance publique - Hôpitaux de Marseille

Marseille, , France

CHU Montpellier

Montpellier, , France

CHU Nantes

Nantes, , France

Assistance publique - Hôpitaux de Paris - Groupe Hospitalier Pitié Salpétrière

Paris, , France

Assistance publique - Hôpitaux de Paris - Hôpital Necker - Enfants malades

Paris, , France

CHU Rennes

Rennes, , France

CHU Rouen

Rouen, , France

CHU Strasbourg

Strasbourg, , France

Countries

France

References

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Reference Type: BACKGROUND

PMID: 35178068 (View on PubMed)

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.

Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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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.

Reference Type: BACKGROUND

PMID: 36846113 (View on PubMed)

El Chehadeh S, Heide S, Quelin C, Rio M, Margot H, Genevieve D, Isidor B, Goldenberg A, Guegan C, Lesca G, Willems M, Ormieres C, Caumes R, Busa T, Bonneau D, Guerrot AM, Marey I, Vera G, Marzin P, Philippe A, Garde A, Coubes C, Vincent M, Michaud V, Mignot C, Charles P, Sigaudy S, Edery P, Lacombe D, Boland A, Nowak F, Bouctot M, Humbert-Asensio ML, Simon A, Chennen K, Sabour N, Delmas C, Nicolas G, Saugier-Veber P, Lecoquierre F, Cassinari K, Keren B, Courtin T, De Sainte Agathe JM, Malan V, Barcia G, Tran Mau-Them F, Safraou H, Philippe C, Thevenon J, Chatron N, Januel L, Piton A, Haushalter V, Gerard B, Lejeune C, Faivre L, Sanlaville D, Heron D, Odent S, Nitschke P, Schluth-Bolard C, Lyonnet S, Deleuze JF, Binquet C, Dollfus H; DEFIDIAG study group. Genome sequencing for the diagnosis of intellectual disability as a paradigm for rare diseases in the French healthcare setting: the prospective DEFIDIAG study. Genome Med. 2025 Oct 3;17(1):110. doi: 10.1186/s13073-025-01527-4.

Reference Type: DERIVED

PMID: 41044778 (View on PubMed)

Other Identifiers

2018-A00680-55

Identifier Type: OTHER

Identifier Source: secondary_id

C16-110

Identifier Type: -

Identifier Source: org_study_id