Genetic architecture of dystonia

The dystonia syndromes are diverse in clinical presentation and show a complex genetic background. The aim of this thesis was to shed light on the genetic architecture of primary dystonias and identify causal and phenotype-modifying genetic variants. We formed a prospective dystonia patient cohort with comprehensive clinical data and collected DNA. In this large cohort various subgroups were identified. These subgroups might prove very useful in gene discovery. With whole exome sequencing combined with linkage analysis in a Myoclonus Dystonia family with orthostatic myoclonus and cardiac arrhythmia we identified a rare missense variant in the 1B subunit of a neuronal type calcium channels (CACNA1B). In another Myoclonus Dystonia family we found a missense variant in RELN, co-segregating with disease. RELN missense variants were also present in two other Myoclonus Dystonia families. Reelin is import for cortical layering and plasticity. In focal dystonia patients, common genetic variants were studied. Here, we did not find new associations with dystonia, though a significantly higher frequency of arm tremor was present in cervical dystonia patients with the plasticity related BDNF Met66Met genotype compared to Val66 carriers (p=0.02). This finding contributes to the idea that common genetic variants could modulate the clinical presentation of dystonia. Lastly, we performed a pilot study with extensive parallel sequencing in a (non-familial) phenotype extreme cohort, and found rare genetics variants in the dopamine receptor D1, possible causal for dystonia