Identifying new repeat expansions and structural variants in autosomal dominant cerebellar ataxias

- Elucidate the genetic cause of "unsolved" ADCA patients and identify new genes and pathomechanisms of ADCAs.

About 30 - 50% of all autosomal dominant cerebellar ataxias (ADCA) remain without a genetic diagnosis despite whole-exome sequencing. With this project, we want to elucidate the genetic cause of these "unsolved" patients and identify new genes and pathomechanisms of ADCAs. We will specifically address the implicit limitations of short-read sequencing techniques and search for new repeat expansions (REs) and new structural variants.

In a first step, we will apply long-read genome sequencing to all unsolved Tübingen ADCA index cases (about 100). To identify REs, a new bioinformatics algorithm will be developed and trained based on local datasets. In a second step, identified RE candidates will be validated in additional unsolved ADCA cases from collaboration partners. Based on a specifically designed CRISPR targeted sequencing approach, it will be possible to screen up to 100 additional cases from different centers for potential new REs and additionally for rare and often not tested RE SCAs, like SCA10, SCA31, SCA36 and SCA37.

Cohorts used ADCA (unsolved, SCA10, 31, 36, & 37)
Funding available? DFG funding (HE 8803/1-1 | OS 647/1-1)
Trial readiness category 1:   basic prerequisites for trial readiness

We’re looking for: molecularly unsolved ataxia cases with autosomal dominant family history and availability of high-quality DNA

Contact persons:
Holger Hengel
Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany

Further project partners:
Stephan Ossowski
University of Tübingen, Tübingen, Germany
Ludger Schöls
University of Tübingen, Tübingen, Germany