Overarching Aims
  • Systematically address and revisit the issue of “reduced penetrance” using hereditary movement disorders as an example
  • Discover mechanisms explaining reduced penetrance in a multimodal fashion
  • Develop bioinformatics and statistical tools, new ethics standards, and a sustainable Knowledge Base for the members of the Research Unit and the scientific community
  • Advancement of ethics methodology for enrolling clinically unaffected mutation carriers in studies aimed at understanding reduced penetrance
Long-Term Scientific Aims
  • Employ additional ‘omics’ approaches and (animal) models to validate findings
  • Identify and functionally characterize non-coding variants relevant for reduced penetrance or for delaying disease expression
  • Focus on epigenetic mechanisms as a likely additional important modifier of penetrance
  • Build on newly identified modifiers of reduced penetrance to gain mechanistic insight through functional studies
  • Extend and further deepen phenotyping by including neuroimaging and electrophysiology techniques (endophenotyping), as well as data on environmental factors
  • Translate findings into genetic counseling routines
  • Explore newly identified genomic factors relevant for the reduction in penetrance as potential therapeutic targets


The figure below shows the interaction between the projects of the Research Unit. Projects P1-P8 all address different aspects of reduced penetrance in movement disorders with a focus on Parkinson’s disease (blue), monogenic dystonia (red), dystonia-parkinsonism (purple), dystonia in general (pink), or method development/analysis (gray). (A) Data from all projects are continuously provided by, and fed back to, the Central Cohort Project (Z2) and to the Central Knowledge Base (INF). Likewise, data from INF (both from the literature and own preliminary or newly generated) will inform additional queries to Z2; conversely, all available and newly collected data will further complement INF with similar feedback mechanisms to and from P1-P8. Z1 serves as central coordination project of the entire Research Unit. (B) In addition, there will be direct interactions between projects P1-P8.

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