Mitochondrial Diseases - Long-read Genome and Transcriptome Sequencing in Cases Unresolved After Short-read Genomics

Genetic Predisposition, Rare Diseases

Rare Diseases, Genetic Predisposition, Epigenetic variation, Omics, Genetic variation, Mitochondrial disease, Next Generation Sequencing (NGS)

The MiDiSeq project will enroll 20 unresolved index patients with suspected mitochondrial disease prioritized for genomic analysis.

In the MiDiSeq (monocentric, prospective, open-label diagnostic) project, patients with suspected mitochondrial disease prioritized for i) high a priori probability for a genetic basis (e.g. positive family history) as well as availability of (ii) fibroblast cell lines with a biochemically defined phenotype, (iii) parental samples, (iv) short read whole genome and transcriptome datasets and (v) optional additional metabolomics and proteomics data. The following questions will be leading the project: i) to systematically benchmark different sequencing technologies to detect genetic and epigenetic variation and their impact on gene regulation. (ii) to further develop algorithms for integrative analyses of different 'omics datasets. (iii) to expand the analysis from coding Single-Nucleotide Variants (SNVs) and regulatory mutations to structural variants (SVs), repeat expansions and contractions, low complexity regions and epigenetic signatures. (iv) to identify novel alterations and disease mechanisms. (v) to gain fundamental new insights into disease mechanisms and cellular biology. (vi) to improve genetic diagnostics of future rare disease patients and to evaluate personalized therapeutic options.

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