Novel diagnostic strategies and data science

Whole genome sequencing (WGS) have been established by several GENOMIC partners. However, even after WGS >40% of the analyzed MD cases remained without a molecular diagnosis. Our established multi-omics approaches helped to further increase the diagnostic rate up to 60%. Still, the multi-omics approach for the characterization of variant consequences faces some limitations, such as low-level somatic mutations, Pathogenic variants with reduced penetrance and polygenic risk factors, which will be addressed by this work package.

We will leverage the available data of multi-omics analysis and cell lines and follow three areas to further improve the diagnostic rates and advance our understanding of mitochondrial pathomechanisms to the benefit of as many MD patients as possible.

This work package is lead and coordinated by Klinikum rechts der Isar (IHG TUM-MED, Munich, Germany) and the Fondazione IRCCS Istituto Neurologico C. Besta (BESTA, Milan, Italy). The cooperating partner are Institute Imagine INSERM (Imagine, Paris, France), Consorcio Centro de Investigación Biomédica en Red (CIBER, Madrid, Spain), Friedrich-Baur-Institute of LMU Munich (LMU, Munich, Germany), The Neurological Institute of the University of Pisa (Pisa, Italy), Department of Informatics of TU Munich (TUM, Munich, Germany), Chiba Children’s Hospital (CCH, Chiba, Japan) and Medical School of Newcastle University (UNEW, Newcastle, Great Britain).

The patient organisation International Mito Patients (IMP, Zwolle, Netherlands) will support the patient recruitment and disseminate results to patients.

MD-specific episignatures and metabolic profiles

Disease-specific metabolic and, most recently, epigenetic signatures are established to initiate genetic testing or validate genetic findings. GENOMIT aims to facilitate and prompt clinical trials for improved disease management approaches by establishing specific outcome measures and identifying novel therapeutic targets. Each new biomarker will also provide novel insights into the pathophysiology of the underlying disorder.

This WP will leverage potentially the largest collection of MD patient biosamples, laboratory measurements and clinical data (phenotyping, disease endpoints, PROMs, and treatment information) to search for biomarkers using genome-wide DNA methylation profiling and high-throughput metabolomics and lipidomics data.

This work package is lead and coordinated by Consorcio Centro de Investigación Biomédica en Red (CIBER, Madrid, Spain) and Western University (WU, London, Canada). Cooperating partners of WP 2 are Luxembourg Centre für Systems Biomedicine (LCSB, Luxembourg), Klinikum rechts der Isar (IHG TUM-MED, Munich, Germany) and all those of WP1.

Assays for functional validation of MD genes

Characterization of variants of uncertain significance is the main limitation of genetic diagnostics by NGS. Mitochondrial Diseases (MDs) are the most heterogeneous group of metabolic diseases with hundreds of involved reactions making conformational tests challenging. Omics-Analysis usually give partial evidence about the effects of the identified variants, but often confirmation is required by targeted assays in either patient samples or model systems.

To close this gap tRNA-sequencing as new diagnostic tool and specific enzyme assays will be developed. Furthermore, complementation studies in models for novel MDs and integration of functional data into existing GENOMIT bioinformatic tools will be performed.

This work package is lead and coordinated by Salzburger Landeskliniken (SALK, Austria) and the Institute Imagine INSERM (Imagine, Paris, France). The cooperation partners are all those of WP2.