Transcriptomic Analysis of Fibroblasts and Blood in Patients With Rare Diseases (ARNseqFibroSan)

Transcriptomic Analysis (RNAseq) of Blood and Fibroblasts to Establish a Diagnosis in Patients With Rare Diseases

This study aims to answer a key question in the field of rare genetic diseases by determining the prevalence of deleterious variants at RNA level in undiagnosed patients with intellectual disability and/or neonatal hypotonia. This study will put an end to diagnostic erraticism in a number of patients.

Finally, the results of this study will make it possible to compare the two types of tissue used for RNAseq, with a view to facilitating the implementation of this analysis method in the diagnostic setting.

Study Overview

• Status: Recruiting
• Conditions: Rare Genetic Disease
• Intervention / Treatment: Procedure: Blood collection; Procedure: skin biopsy

Detailed Description

Rationale:

The majority of patients with intellectual disability or neonatal hypotonia remain undiagnosed, despite extensive genetic testing. In fact, standard analyses aimed at detecting abnormalities in the patient's DNA only enable a diagnosis to be made in a third of cases. Our hypothesis is that a certain number of these misdiagnosed patients carry anomalies (pathogenic variants) disrupting the RNA (transcript), which were not identified by DNA sequencing.

This study aims to answer a key question in the field of rare genetic diseases by determining the prevalence of deleterious variants at RNA level in undiagnosed patients with intellectual disability and/or neonatal hypotonia. This study will put an end to diagnostic erraticism in a number of patients.

Finally, the results of this study will make it possible to compare the two types of tissue used for RNAseq, with a view to facilitating the implementation of this analysis method in the diagnostic setting.

Objectives:

Determine the prevalence of variants with a deleterious effect at RNA level, identified by transcriptomic analysis (RNAseq) in diagnostically errant patients with neonatal hypotonia and/or intellectual disability. This analysis will be carried out in parallel on blood and fibroblast culture (skin biopsy).

Compare the number of pathogenic variants identified by RNAseq on blood tissue with the number of pathogenic variants identified by RNAseq on fibroblast culture. The result will help to decide whether a single sample is sufficient to obtain a diagnosis in patients in diagnostic limbo.

Study endpoints:

The number of patients initially in diagnostic errancy in whom a deleterious variant at RNA level was identified by transcriptomic analysis (RNAseq).

The number of deleterious RNA variants identified in patients in diagnostic errancy using ARNseq on fibroblasts and the deleterious RNA variants identified using ARNseq on blood samples.

Study design:

Multicentric descriptive prevalence study

Study Procedures:

Patients (or their parents in the case of minors) will be informed of the possibility of participating in the study during a follow-up consultation as part of their usual care. Patients will also be given a leaflet explaining the study. After a period of reflection, patients will be seen at one of three centers (Marseille, Toulon, Nice) to sign a consent form and take samples.

Only one visit is planned as part of the study. This is the inclusion visit, during which skin and blood samples are taken.

If a pathogenic variant explaining the phenotype is identified in a patient, the patient's physician will request confirmation of the variant by targeted analysis (Sanger sequencing) by the laboratory (Laboratoire de Génétique Moléculaire, APHM) as part of the diagnosis. This result will be provided by the patient's doctor as part of the patient's usual care.

Subjects number: 62

Study Timelines:

Inclusion period: 36 months Duration of follow-up: There is no follow-up for the patient in this study - a single inclusion visit is planned. Results will be reported as part of the patient's usual care.

Duration of analyses: 6 months Total duration (duration of inclusion and duration of analysis): 42 months

• Study Type: Interventional
• Enrollment (Estimated): 62
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Svetlana GOROKHOVA, MD; Phone Number: 33491388499; Email: svetlana.gorokhova@ap-hm.fr

Study Locations

• France
  • Provence-Alpes-Côt-d'Azue
    • Marseille, Provence-Alpes-Côt-d'Azue, France, 13354
      • Recruiting
      • Assistance Publique - Hôpitaux de Marseille
      • Contact: Svetlana GOROKHOVA, MD; Phone Number: 33491388499; Email: svetlana.gorokhova@ap-hm.fr
      • Principal Investigator: Svetlana GOROKHOVA, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Male or female, aged 0-99 years
• Patient with neonatal intellectual disability and/or hypotonia followed at one of three inclusion centers
• Patient or parent has been informed about the study and has signed an informed consent form
• Genetic analysis by high-throughput DNA sequencing (gene panel, exome, genome) did not identify any abnormality explaining the patient's phenotype.
• If the patient's phenotype is suggestive of Prader-Willi syndrome or Angelman syndrome: a methylation anomaly test on chromosome 15 was negative.
• If the patient's phenotype is suggestive of fragile X syndrome: a repeat expansion analysis of the FMR1 gene was negative.
• If the patient's phenotype is suggestive of myotonic dystrophy type I, DM1: a repeat expansion analysis of the DMPK gene was negative.
• Patient entitled to or beneficiary of a social security scheme

Exclusion Criteria:

• Patient deprived of liberty
• Pregnant or breast-feeding woman,
• The person required to sign the consent form does not understand French
• Person under guardianship and/or curatorship

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

Experimental: ARNseq; Patients enrolled in the experimental arm will be seen in consultation to sign the consent form and take samples at one of the participating investigational sites. Only one visit is planned as part of the study. This is the inclusion visit, during which skin and blood samples are taken. If a pathogenic variant explaining the phenotype is identified in a patient, the clinician following the patient will request confirmation of the variant by targeted analysis (Sanger sequencing) as part of the diagnosis. This result will be returned by the clinician who follows the patient as part of his or her usual care.

Procedure: Blood collection; Blood is collected in order to perform transcriptomic sequencing from blood; Procedure: skin biopsy; A biopsy of skin is performed in order to perform transcriptomic sequencing on fibroblasts obtained from the biopsy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patients with identified deleterious variant at RNA level	The number of patients initially in diagnostic errancy in whom a deleterious variant at RNA level was identified by transcriptomic analysis (RNAseq).	Through study completion, an average of 42 month.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of the number of variants obtained from blood and from fibroblasts	Number of deleterious RNA variants identified in patients with diagnostic errancy using ARNseq on fibroblasts and deleterious RNA variants identified using ARNseq on blood samples	Through study completion, an average of 42 month.

Collaborators and Investigators

• Sponsor: Assistance Publique Hopitaux De Marseille

Study record dates

Study Major Dates

• Study Start (Actual): March 9, 2026
• Primary Completion (Estimated): April 30, 2029
• Study Completion (Estimated): April 30, 2029

Study Registration Dates

• First Submitted: May 22, 2025
• First Submitted That Met QC Criteria: July 10, 2025
• First Posted (Actual): July 20, 2025

Study Record Updates

• Last Update Posted (Actual): May 8, 2026
• Last Update Submitted That Met QC Criteria: May 4, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Genomic Testing; Intellectual disability; Rare diseases; genetic analysis by high-throughput DNA sequencing; ARNseq; transcriptomic data; interpretation of sequence variants; RNA sequencing data; transcriptome analysis in rare disease
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Pathologic Processes; Disease Attributes; Neurobehavioral Manifestations; Neurodevelopmental Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Rare Diseases; Intellectual Disability; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Blood Specimen Collection
• Other Study ID Numbers: RCAPHM23_0469; ID-RCB (Other Identifier: 2025-A02239-40)

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