Etude Pilote Des différentes stratégies de séquençage Haut débit du génome Pour le Diagnostic génétique Des Patients Atteints de déficience Intellectuelle
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 3,825
- 试验地点
- 27
- 主要终点
- Diagnostic Yield
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Diagnostic
- 盲法
- None (Outcomes Assessor)
盲法说明
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.
入排标准
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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:
- •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
排除标准
- 未提供
结局指标
主要结局
Diagnostic Yield
时间窗: 12 months
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.
次要结局
- Median time and type of skills required for analyzing genetic data and for genetic confirmation(12 months)
- Incremental cost-effectiveness ratio(24 months)
- Number and type of secondary data(12 months)
- Causal structural change(12 months)
- Mean cost of wavering diagnostic research(24 months)
- Percentage of at least one modification in medical, medico-social, rehabilitative and psychological follow-up(24 months)
- Median time to obtain results(12 months)