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

Resolving Unsolved Rare Diseases : Functional Tests and New Diagnosis Strategy to Study Genetic Variants From High-throughput Sequencing (RID)

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.

Study Overview

• Status: Recruiting
• Conditions: Intellectual Disability; Cystic Fibrosis; Neurodegeneration With Brain Iron Accumulation (NBIA); Congenital Heart Defect; Albinism; Rubinstein-Taybi Syndrome; Periventricular Nodular Heterotopia
• Intervention / Treatment: Genetic: Ex-vivo approach concerning 25 patients; Genetic: In-vitro approach concerning 25 patients

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.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Vincent MICHAUD; Phone Number: +335 57 82 01 93; Email: vincent.michaud@chu-bordeaux.fr
• Study Contact Backup: Name: Ndeye-Fatou NGOM; Email: ndeye-fatou.ngom@chu-bordeaux.fr

Study Locations

• France
  • Bordeaux, France, 33000
    • Recruiting
    • Hopital Pellegrin
    • Contact: Vincent MICHAUD, Dr; Email: vincent.michaud@chu-bordeaux.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 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	Genetic: Ex-vivo approach concerning 25 patients; Ex-vivo approach concerning 25 patients with blood sample in PAXgene tubes or skin biopsy and RNA-Seq analysis; Genetic: In-vitro approach concerning 25 patients; In-vitro approach concerning 25 patients without specific samples needed for analysis in minigene or luciferase assay

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Inclusion visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Inclusion visit
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.	Inclusion visit
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	Inclusion visit
Praticability : Training time of Biologists for interpretation	Evaluation of training time needed to interpret the data	Inclusion visit
Global cost	Evaluation of cost of global analyse and each test	Inclusion visit

Collaborators and Investigators

• Sponsor: University Hospital, Bordeaux
• Investigators: Principal Investigator: Vincent MICHAUD, University Hospital, Bordeaux

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2023
• Primary Completion (Estimated): February 1, 2025
• Study Completion (Estimated): February 1, 2025

Study Registration Dates

• First Submitted: December 7, 2022
• First Submitted That Met QC Criteria: January 23, 2023
• First Posted (Actual): January 25, 2023

Study Record Updates

• Last Update Posted (Estimated): February 21, 2024
• Last Update Submitted That Met QC Criteria: February 20, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: RNAseq; Translational research; Variant of unknown significance; Functional genetics; Gene expression regulation
• Additional Relevant MeSH Terms: Mental Disorders; Digestive System Diseases; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Skin Diseases; Respiratory Tract Diseases; Lung Diseases; Eye Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Disease Attributes; Congenital Abnormalities; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Musculoskeletal Diseases; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Skin Diseases, Genetic; Eye Diseases, Hereditary; Bone Diseases; Metabolism, Inborn Errors; Heredodegenerative Disorders, Nervous System; Neurodevelopmental Disorders; Pancreatic Diseases; Amino Acid Metabolism, Inborn Errors; Cardiovascular Abnormalities; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Malformations of Cortical Development; Nervous System Malformations; Abnormalities, Multiple; Chromosome Disorders; Pigmentation Disorders; Bone Diseases, Developmental; Hypopigmentation; Neuroaxonal Dystrophies; Dysostoses; Malformations of Cortical Development, Group II; Cystic Fibrosis; Heart Defects, Congenital; Intellectual Disability; Pantothenate Kinase-Associated Neurodegeneration; Nerve Degeneration; Rare Diseases; Albinism; Rubinstein-Taybi Syndrome; Periventricular Nodular Heterotopia
• Other Study ID Numbers: CHU BX 2021/40

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No