Identification of molecular causes of mitochondrial defects by personalised omics approaches

Understanding the chain of molecular events that causes a disease is a prerequisite to develop rational molecular medicine. Molecular diagnosis is challenging because every patient has a unique genetic background and it is not often possible to discriminate between causal and correlative associations among gene variants, transcripts, proteins and metabolites. Here, we will develop and validate systematic approaches to infer the molecular bases of mitochondrial diseases in individual patients by combining genetics, functional genomics, and statistical causal inference. Recently, we have applied exome sequencing to pinpoint causal mutations in more than one hundred patients with severe mitochondrial defects. Nevertheless, little is known about the cellular cascades and mechanisms leading to their pathologies. Furthermore, about half of our patients still fail to receive a firm genetic diagnosis. To identify causal mutations and functionally impaired pathways in patients with mitochondrial dysfunctions, we will combine whole-genome sequencing, transcriptome profiling and genome-wide functional genomics screens. Statistical causal inference based on modelling genotype, gene expression, and phenotype, or from detecting interactions between gene knock-down and genetic background, will indicate candidate causal mutations and affected pathways for each patient. The network consists of three Munich-based young independent investigators with complementary expertise:

  • Dr. Fabiana Perocchi, Biologist, (Helmholtz center / Gene center of the LMU)
  • Dr. Tobias Haack, medical doctor (University hospital Tübingen)
  • Julien Gagneur, applied mathematician (grant coordinator, TU Munich)

Our pilot study will establish protocols and algorithms for personalized genomics. In close partnership with a large European network of mitochondrial clinicians (mitoNET), we aim at translating these methodologies into clinical routine by offering new diagnostic tools and providing a better understanding of the molecular bases of inherited mitochondrial disorders.

An interdisciplinary team anchored in a European network

Subprojects in mitOmics:

SP 3    Integrative analysis to infer mutations and pathways causal for the disease

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