MITOMICS : a Multi-OMICS Approach for the Diagnosis of Mitochondrial Diseases

Mitochondrial Diseases Clinical Trial

— MITOMICS  

Official title:

Interest of Multi-omics (WES / RNA-Seq) Approach to Fight Against the Diagnostic Deadlock in Mitochondrial Diseases

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04920812
• Other study ID #: 19-API-01
• Secondary ID: 2020-A02651-38
• Status: Recruiting
• Start date: March 7, 2022
• Est. completion date: September 7, 2025

Study information

• Verified date: January 2024
• Source: Centre Hospitalier Universitaire de Nice
• Contact: SYLVIE BANNWARTH
• Phone: 0492034702
• Email: bannwarth.s[@]chu-nice.fr
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

MITOMICS aims to determine which RNA-Seq results (from muscle or fibroblasts) are the most informative for the interpretation of VUS identified by WES for patients suspected of mitochondrial myopathy. Analysis of RNA-Seq and WES results will performed with a computational approach using an autoencoder-based method

Description:

Mitochondrial diseases (MD) are rare, clinically and genetically extremely heterogeneous, caused by a deficit of energy production via the mitochondria. Mitochondria are dependent on 2 genomes mitochondrial DNA and nuclear DNA, and many pathogenic variants carried by these 2 genomes are responsible for mitochondrial diseases. The diagnostic strategies for MD patients have evolved significantly with the emergence of Next Generation Sequencing (NGS) also accelerating the identification of the responsible gene. However, the diagnostic yield remains limited and requires the development of new approaches. Previous studies showed that WES and RNA-Seq combination improves the diagnosis of MD, essentially by helping in the interpretation of identified VUS.

With MITOMICS project, we will included 66 patients suspected of a mitochondrial myopathy (clinical, histological or biochemical), with a negative mtDNA and WES NGS in trio. For each patient we will sequenced RNA from muscle and fibroblasts. Using a new innovative methology of multi-OMICS integration we will determined which RNA-Seq data (from muscle or fibroblasts) are the most informative for the interpretation of VUS identified by WES for patients suspected of mitochondrial myopathy. The results obtained will allow the interpretation of VUS and the identification of specific molecular signatures.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 66
• Est. completion date: September 7, 2025
• Est. primary completion date: March 7, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 0 Days and older

Eligibility

Inclusion Criteria:

• Patients suspected of a mitochondrial disease with muscular signs (clinical, histological or biochemical)

• Patients with negative mtDNA and WES NGS in trio

• Patients with routine muscle and skin biopsies available

• Blood samples from parents and / or relatives available for segregation studies

• Informed consent of the study signed by the patient or the legal representatives of the minor patient or under guardianship

• Patients affiliated to social security

Exclusion Criteria:

• Patients with suspected mitochondrial disease without muscle involvement

• Patients for whom the mtDNA NGS and WES have not been performed

• Patients with suspected mitochondrial disease with causal variant identified

• Refusal to sign the informed consent for the study

• Insufficient amount of frozen material or culture failure for fibroblasts

Related Conditions & MeSH terms

• Mitochondrial Diseases

Intervention

Genetic:
• diagnosis of mitochondrial myopathy
• Determination of the presence of specific molecular signatures at the RNA level in muscles and fibroblasts from patients

Locations

Country	Name	City	State
France	chu Angers	Angers
France	C.H.R.U. Brest	Brest
France	APHM	Marseille
France	Chu de Nantes	Nantes
France	CHU de Nice	Nice	Chu de Nice

Sponsors (1)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire de Nice

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	number of variations interpreted as responsible for the Mitochondrial diseases	• Comparison of the number of variations (splicing variant, expression level) or VUS, identified in WES, interpreted as responsible for the disease (class 4 or 5 variants) thanks to (i) the RNA-Seq carried out at from a muscle biopsy or (ii) RNA-Seq performed from fibroblasts	baseline
Secondary	RNA in mitochondiral deseases	Patients for whom the RNA-Seq could not be performed and reason for failure	baseline
Secondary	variation of RNA in mitochondiral deseases	Variations identified by RNA-Seq, allowing interpretation of WES data (splicing aberrants, monoallelic expressions, etc.)	baseline
Secondary	specific molecular signatures of mitochondiral deseases	Determination of the presence of specific molecular signatures at the RNA level in muscles and fibroblasts from patients	baseline