SP5: Elucidation of novel genetic causes for dystonia
Dystonias are genetically highly heterogeneous. Within the past 20 years, several genetic, mostly autosomal dominantly inherited forms have been identified. The known dystonia (DYT) genes such as TOR1A, THAP1, or GCH1, are linked to diverse pathways and neuronal functions including dopamine signaling, transcriptional control, and intracellular transport. Recently, with the advent of next generation sequencing (NGS), novel dystonia genes have been elucidated including KMT2B and ANO3.
Importantly, additional genes remain to be found for dystonia since in many patients - despite high heritability - the disease cannot be explained by mutations in known genes. Further, even for the known genes, the phenotypic and genotypic spectrum as well as the prevalence and relevance of mutations need to be fully elucidated to enable more precise genetic counselling including predictions of the disease course.
To fill these gaps in our current knowledge of this rare disorder additional research in warranted. The focus of our study is on novel dystonia genes as well as on the investigation of known genetic forms in the Dystonia Registry. Therefore, we use two different applications of NGS to shed more light on genetic causes of dystonia. Specifically, (1) we are using exome sequencing in selected families to unravel novel dystonia genes. And (2), we established an NGS-based gene panel for parallel investigation of known dystonia genes in more than 1000 samples from the German Dystonia Registry.
Mutation carriers are being included in other subprojects of the consortium to address the disease mechanism on the molecular and/or electrophysiological level.
Using next generation sequencing (NGS), we aim to address two important unsolved questions in the genetics of dystonia, e. g.
- Identification of novel disease genes. For this, we will elucidate the genetic cause in 10 families with dystonia by exome sequencing. We will focus on patients with childhood onset and severe forms of dystonia with unaffected parents (trios) and propose a de-novo mutation as the disease cause.
- Identification of additional mutation carriers. We will screen the samples from the German Dystonia Registry (subproject 2) for mutations in known genes to characterize the cohort and to elucidate the relevance of known genes. For this, we will use a gene panel and NGS.