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Christian–Albrechts–Universität zu Kiel
Institut für Medizinische Informatik und Statistik

ProtectMove: Reduced Penetrance

While the number of genes discovered to cause human diseases has been growing exponentially as a result of applying next generation sequencing (NGS), an unexpected finding of these major sequencing efforts was the surprisingly large proportion of carriers of an allegedly pathogenic mutation who do not develop the disease in question. This phenomenon is commonly referred to as ‘reduced penetrance', a conundrum well documented in hereditary diseases and initially evidenced by case and family studies of monogenic disorders.

The scope of this phenomenon appears to have been substantially underestimated. One of the remarkable discoveries of the 1000 Genomes Project and Exome Aggregation Consortium is that each person carries an average of 50-100 loss-of-function variants previously implicated in inherited diseases.

The overarching goal of the ProtectMove project is to decipher the mechanisms underlying reduced penetrance in neurogenetic model diseases. The primary focus will be laid on Parkinson's disease (PD) and dystonia (DYT), two related movement disorders for which a large number of mutations are known that exhibit a pronounced degree of reduced penetrance. The results obtained from ProtectMove will not only lead to a better understanding of the pathogenic mechanisms underlying disease development and progression, but will also offer new avenues for the prevention and treatment of these disorders.