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

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.

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

Patients are seen in consultation by the genetic doctors of the different centers as part of the usual management of their mitochondrial disease.