Resolving Unsolved Rare Diseases : Functional Tests and New Diagnosis Strategy to Study Genetic Variants From High-throughput Sequencing (RID)
Overview
- Phase
- N/A
- Intervention
- Not specified
- Conditions
- Intellectual Disability
- Sponsor
- University Hospital, Bordeaux
- Enrollment
- 50
- Locations
- 1
- Primary Endpoint
- Proportion of VOUS reclassified as pathogenic (class 5) or benign (class 1)
- Status
- Recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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)
Exclusion Criteria
- •Refusal to participate in research protocol.
- •Patient under administrative supervision
- •Pregnant or nursing women
Outcomes
Primary Outcomes
Proportion of VOUS reclassified as pathogenic (class 5) or benign (class 1)
Time Frame: 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
Secondary Outcomes
- 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)