Clinical trial NCT05696912: Functional Tests to Resolve Unsolved Rare Diseases. Rares.
Official title: Resolving Unsolved Rare Diseases : Functional Tests and New Diagnosis Strategy to Study Genetic Variants From High-throughput Sequencing (RID)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: 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
Lead sponsor: University Hospital, Bordeaux
Sponsor class: OTHER
First posted: 2023-01-25
Enrollment: 50
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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.
Primary purpose: DIAGNOSTIC

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.

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

Primary outcomes:
measure: Proportion of VOUS reclassified as pathogenic (class 5) or benign (class 1)
timeFrame: Inclusion visit
Secondary outcomes:
measure: Pre-analysis process : Time of sample transport to the laboratory
timeFrame: Inclusion visit
measure: Pre-analysis process : Quality of RNA extraction (RNA Integrity Number, RIN)
timeFrame: Inclusion visit
measure: Praticability :Characteristics and number of CPU (Central Processing Unit)
timeFrame: Inclusion visit
measure: Praticability : Training time of Biologists for interpretation
timeFrame: Inclusion visit
measure: Global cost
timeFrame: Inclusion visit
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Hopital Pellegrin
Study officials:
affiliation: University Hospital, Bordeaux
name: Vincent MICHAUD
role: PRINCIPAL_INVESTIGATOR
References: