Looking for RNA clues in blood and skin to find causes of rare genetic conditions

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

This will test whether RNA sequencing of blood and skin cells can find hidden genetic changes in people of any age with unexplained intellectual disability or neonatal hypotonia.

Quick facts

• Phase: Not applicable
• Study type: Interventional
• Enrollment: 62 (estimated)
• Ages: 0 Years to 99 Years
• Sex: All
• Sponsor: Assistance Publique Hopitaux De Marseille (Academic / other)
• Locations: 1 site (Marseille, Provence-Alpes-Côt-d'Azue)
• Trial ID: NCT07075107 on ClinicalTrials.gov

What this trial studies

Many patients with intellectual disability or neonatal hypotonia remain undiagnosed after standard DNA testing, and researchers hypothesize that some cases are caused by RNA-level defects. This study collects blood and skin biopsy samples (cultured fibroblasts) from undiagnosed patients and performs transcriptomic (RNAseq) analysis on both tissues. The number and type of deleterious RNA-level variants found in each tissue will be compared to determine which sample is more informative. Results aim to estimate how often RNA-level defects explain previously unexplained cases and to guide implementation of RNAseq in diagnostic practice.

Who should consider this trial

Good fit: Ideal candidates are people (age 0–99) with intellectual disability and/or neonatal hypotonia whose prior high-throughput DNA testing (gene panel, exome, or genome) did not find a cause and who can attend the Marseille center for blood draw and skin biopsy.

Not a fit: People who already have a confirmed genetic diagnosis explaining their symptoms, those unable or unwilling to provide a skin biopsy, pregnant or breastfeeding women, and people deprived of liberty are unlikely to benefit.

Why it matters

Potential benefit: If successful, this approach could provide genetic diagnoses for patients who previously had no explanation for their condition, shortening the diagnostic odyssey and informing care.

How similar studies have performed: Previous research has shown that RNA sequencing can reveal splice or expression defects missed by DNA tests and can increase diagnostic yield in rare disease cohorts, so this approach has promising precedent.

Eligibility criteria

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

Where this trial is running

Marseille, Provence-Alpes-Côt-d'Azue

• Assistance publique - hôpitaux de Marseille — Marseille, Provence-Alpes-Côt-d'Azue, France (Recruiting)

Study contacts

• Study coordinator: Svetlana GOROKHOVA, MD

Conditions Rare Genetic Disease; genetic analysis by high-throughput DNA sequencing; ARNseq; transcriptomic data; interpretation of sequence variants; Genomic Testing; RNA sequencing data; transcriptome analysis in rare disease