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Functional Tests to Resolve Unsolved Rare Diseases. Rares. (RID)

Primary Purpose

Intellectual Disability, Rubinstein-Taybi Syndrome, Cystic Fibrosis

Status
Recruiting
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Ex-vivo approach concerning 25 patients
In-vitro approach concerning 25 patients
Sponsored by
University Hospital, Bordeaux
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Intellectual Disability focused on measuring Variant of unknown significance, Functional genetics, Translational research, RNAseq, Gene expression regulation

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Hopital PellegrinRecruiting

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Ex-vivo and In-vitro approach

Arm Description

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

Outcomes

Primary Outcome Measures

Proportion of VOUS reclassified as pathogenic (class 5) or benign (class 1)
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 Outcome Measures

Pre-analysis process : Time of sample transport to the laboratory
Time of transport to the laboratory. To calculate this time, the time of collection and the time of receipt by the and the time of reception by the molecular genetics technician will be recorded
Pre-analysis process : Quality of RNA extraction (RNA Integrity Number, RIN)
RNA quality measurement by RIN (RNA integrity number): very good >7, good >/=5, poor <5. Only RNA with RIN >5 will be retained.
Praticability :Characteristics and number of CPU (Central Processing Unit)
Evaluation of bioinformatic ressources by measure of number of CPU needed and turnaround time for processing data
Praticability : Training time of Biologists for interpretation
Evaluation of training time needed to interpret the data
Global cost
Evaluation of cost of global analyse and each test

Full Information

First Posted
December 7, 2022
Last Updated
February 10, 2023
Sponsor
University Hospital, Bordeaux
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1. Study Identification

Unique Protocol Identification Number
NCT05696912
Brief Title
Functional Tests to Resolve Unsolved Rare Diseases. Rares.
Acronym
RID
Official Title
Resolving Unsolved Rare Diseases : Functional Tests and New Diagnosis Strategy to Study Genetic Variants From High-throughput Sequencing (RID)
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 30, 2023 (Actual)
Primary Completion Date
February 2024 (Anticipated)
Study Completion Date
February 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Bordeaux

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Intellectual Disability, Rubinstein-Taybi Syndrome, Cystic Fibrosis, Congenital Heart Defect, Periventricular Nodular Heterotopia, Neurodegeneration With Brain Iron Accumulation (NBIA), Albinism
Keywords
Variant of unknown significance, Functional genetics, Translational research, RNAseq, Gene expression regulation

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Model Description
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.
Masking
None (Open Label)
Allocation
N/A
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Ex-vivo and In-vitro approach
Arm Type
Other
Arm Description
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
Intervention Type
Genetic
Intervention Name(s)
Ex-vivo approach concerning 25 patients
Intervention Description
Ex-vivo approach concerning 25 patients with blood sample in PAXgene tubes or skin biopsy and RNA-Seq analysis
Intervention Type
Genetic
Intervention Name(s)
In-vitro approach concerning 25 patients
Intervention Description
In-vitro approach concerning 25 patients without specific samples needed for analysis in minigene or luciferase assay
Primary Outcome Measure Information:
Title
Proportion of VOUS reclassified as pathogenic (class 5) or benign (class 1)
Description
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
Time Frame
Inclusion visit
Secondary Outcome Measure Information:
Title
Pre-analysis process : Time of sample transport to the laboratory
Description
Time of transport to the laboratory. To calculate this time, the time of collection and the time of receipt by the and the time of reception by the molecular genetics technician will be recorded
Time Frame
Inclusion visit
Title
Pre-analysis process : Quality of RNA extraction (RNA Integrity Number, RIN)
Description
RNA quality measurement by RIN (RNA integrity number): very good >7, good >/=5, poor <5. Only RNA with RIN >5 will be retained.
Time Frame
Inclusion visit
Title
Praticability :Characteristics and number of CPU (Central Processing Unit)
Description
Evaluation of bioinformatic ressources by measure of number of CPU needed and turnaround time for processing data
Time Frame
Inclusion visit
Title
Praticability : Training time of Biologists for interpretation
Description
Evaluation of training time needed to interpret the data
Time Frame
Inclusion visit
Title
Global cost
Description
Evaluation of cost of global analyse and each test
Time Frame
Inclusion visit

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Vincent MICHAUD
Phone
+335 57 82 01 93
Email
vincent.michaud@chu-bordeaux.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Ndeye-Fatou NGOM
Email
ndeye-fatou.ngom@chu-bordeaux.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Vincent MICHAUD
Organizational Affiliation
University Hospital, Bordeaux
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hopital Pellegrin
City
Bordeaux
ZIP/Postal Code
33000
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Vincent MICHAUD, Dr
Email
vincent.michaud@chu-bordeaux.fr

12. IPD Sharing Statement

Plan to Share IPD
No

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Functional Tests to Resolve Unsolved Rare Diseases. Rares.

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