Resolving Unsolved Rare Diseases : Functional Tests and New Diagnosis Strategy to Study Genetic Variants From High-throughput Sequencing (RID)
试验速览
- 阶段
- 不适用
- 发起方
- 入组人数
- 50
- 试验地点
- 2
- 主要终点
- Proportion of VOUS reclassified as pathogenic (class 5) or benign (class 1)
研究概览
简要总结
Rares diseases are a heterogeneous group of conditions which need important tools for diagnosis.
The use of high-throughput sequencing is able to diagnose half of the patients. For the other part it is impossible to conclude due to the presence of variants of unknown significance (VOUS). Functional analysis are needed to bring strong argument to reclassify variants as pathogenic or benign. The main objective is to evaluate the diagnosis yield of this strategy.
详细描述
The main objective is the improvement of the diagnosis of rare genetic diseases. The investigator lab is expert for diagnosis of some rare diseases such as neurodevelopmental disorder, albinism, cystic fibrosis and congenital heart defect. Actually with implementation of high-throughput sequencing for diagnosis, a high number of genetic variants are found and need to be interpretated. The ACMG classification is used to classify variants with argument of variant frequency, predicted effect on protein and in-silico prediction. Functional evidence is a strong argument to help classify VOUS. The investigators propose the use of RNA-Seq, minigene and luciferase assay for study of VOUS to bring argument to classify them as benign or pathogenic.
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
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Minor and adult patient.
- •Registered for the social security system.
- •Informed consent signed by patient or parent of a minor patient.
- •Patient affected by one of the rare diseases studied (albinism, congenital heart defect, cystic fibrosis, neurodevelopmental disease)
- •Patient bearing variants of unknown significance (VOUS)
排除标准
- •Refusal to participate in research protocol.
- •Patient under administrative supervision
- •Pregnant or nursing women
研究组 & 干预措施
Ex-vivo and In-vitro approach
Ex-vivo approach concerning 25 patients with blood sample in PAXgene tubes or skin biopsy and RNA-Seq analysis.
In-vitro approach concerning 25 patients without specific samples needed for analysis in minigene or luciferase assay
干预措施: Ex-vivo approach concerning 25 patients (Genetic)
Ex-vivo and In-vitro approach
Ex-vivo approach concerning 25 patients with blood sample in PAXgene tubes or skin biopsy and RNA-Seq analysis.
In-vitro approach concerning 25 patients without specific samples needed for analysis in minigene or luciferase assay
干预措施: In-vitro approach concerning 25 patients (Genetic)
结局指标
主要结局
Proportion of VOUS reclassified as pathogenic (class 5) or benign (class 1)
时间窗: Inclusion visit
It's the proportion of VOUS that could be definitively reclassified as pathogenic (class 5) or benign (class 1) according to the ACMG classification (Richards et al., 2015 and Appendix 1). Indeed currently only variants considered as pathogenic or probably pathogenic make it possible to confirm a diagnosis and to propose genetic offer genetic counseling to families and perform a prenatal diagnosis. This is an evaluation that will be carried out at the end of the analyses carried out
次要结局
- Pre-analysis process : Time of sample transport to the laboratory(Inclusion visit)
- Praticability :Characteristics and number of CPU (Central Processing Unit)(Inclusion visit)
- Praticability : Training time of Biologists for interpretation(Inclusion visit)
- Global cost(Inclusion visit)
- Pre-analysis process : Quality of RNA extraction (RNA Integrity Number, RIN)(Inclusion visit)