Clinical trial NCT04920812: MITOMICS : a Multi-OMICS Approach for the Diagnosis of Mitochondrial Diseases
Official title: Interest of Multi-omics (WES / RNA-Seq) Approach to Fight Against the Diagnostic Deadlock in Mitochondrial Diseases
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Mitochondrial Diseases
Lead sponsor: Centre Hospitalier Universitaire de Nice
Sponsor class: OTHER
First posted: 2021-06-10
Enrollment: 66
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: OTHER
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients are seen in consultation by the genetic doctors of the different centers as part of the usual management of their mitochondrial disease.

Brief 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

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: number of variations interpreted as responsible for the Mitochondrial diseases
timeFrame: baseline
Secondary outcomes:
measure: RNA in mitochondiral deseases
timeFrame: baseline
measure: variation of RNA in mitochondiral deseases
timeFrame: baseline
measure: specific molecular signatures of mitochondiral deseases
timeFrame: baseline
Other outcomes:
Locations:
city: Nice
country: France
facility: CHU de Nice
state: Chu de Nice
city: Angers
country: France
facility: chu Angers
city: Brest
country: France
facility: C.H.R.U. Brest
city: Brest
country: France
facility: Chu Brest
city: Marseille
country: France
facility: APHM
city: Marseille
country: France
facility: APHM
city: Montpellier
country: France
facility: Chu Montpellier
city: Nantes
country: France
facility: Chu de Nantes
city: Nantes
country: France
facility: CHU Nantes
Study officials:
affiliation: Centre Hospitalier Universitaire de Nice
name: SYLVIE BANNWARTH
role: PRINCIPAL_INVESTIGATOR
References: