#6 Next-generation genomics & platforms

Working Group 6
WG Name Next-generation genomics and platforms
WG Leads Brent Fogel (Los Angeles, USA)
Andrea Nemeth (Oxford, UK)
Matthis Synofzik (Tübingen, Germany)
Stephan Zuchner (Miami, USA)
The goal of this working group is to identify and enrich genetically stratified ataxia patients for trial-readiness natural history studies and treatment trials. This will be achieved by establishing a genetic ataxia diagnosis for as many ataxia patients as possible, in particular for genetically still undefined and “hard-to-diagnose” ataxia patients, and by prioritizing genetic ataxia conditions which are already druggable (e.g. COQ8A ataxia, Niemann Pick Type C ataxia; ataxia patients with splice mutations amenable for n-of-1 ASO treatments) or are currently being prepared for trial-readiness/druggability (e.g. ion channel SCAs, ARSACS, SPG7, etc.).

This will be achieved by work on three parallel project Aims. For ataxia patients still without a genetic ataxia diagnosis, Aim #1 will identify mutations in known ataxia genes by (i) increasing the percentage of unsolved ataxia patients receiving WES/WGS, i.e. generating novel WES/WGS datasets (goal #1); (ii) reanalyzing existing WES/WGS datasets of patients where no causative mutation has been found so far (goal #2); and (iii) clarifying the pathogenicity of VUS in SCA/ARCA genes in still unsolved patients (goal #3). Aim #2 will identify mutations in novel ataxia genes for these undiagnosed patients. It will be based on establishing optimal and novel systematic genomic strategies to identify novel ataxia genes (goal #4). The key to both Aims #1 and #2 will be large-scale cross-center sharing of existing ataxia NGS datasets using three readily mineable collaborative ataxia genomics platforms. Aim #3 will implement ways to incorporate newly genetically diagnosed ataxia patients into existing ataxia trial-readiness registries (SCA registry, ARCA registry, etc.) (goal #5), and to share newly identified potentially treatable genomic mechanisms with other working groups in the AGI (goal #6).

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