ProjectIdentifizierung neuer expandierende Repeat-Erkrankungen bei autosomal-dominanten zerebellären Ataxien

Basic data

Identifizierung neuer expandierende Repeat-Erkrankungen bei autosomal-dominanten zerebellären Ataxien
01/06/2021 to 01/06/2024
Abstract / short description:
Autosomal dominant cerebellar ataxias (ADCAs) are neurogenetic diseases that primarily lead to degeneration of the cerebellum, with progressive incoordination of gait, extremities and speech. Currently about 50 ADCA genes are known. The most common ADCA genotypes worldwide are Spinocerebellar Ataxia Type 3 (SCA3), SCA 1, SCA2, SCA6 and SCA7. These are caused by exonic CAG trinucleotide repeat expansions. Other genotypes are rarer and are usually caused by point mutations in genes that code for many other protein classes in addition to ion channels. Non-coding repeat expansions (REs) are another cause of ADCAs and known REs generally lead to a strikingly high incidence of cerebellar phenotypes. The intronic repeats in the RFC1 gene described in 2019 cause the autosomal recessive CANVAS syndrome. Despite these known genotypes, an estimated 50% of all ADCA patients remain without genetic diagnosis. Also in the Tübingen ADCA cohort, after careful genetic diagnosis including screening for known REs and subsequent exome sequencing, 100 index patients out of 400 ADCA families remain without genetic diagnosis. With this project we want to elucidate the genetic cause of these "unsolved" families and identify new pathomechanisms and genotypes of ADCAs. We will specifically address the implicit limitations of short-read sequencing techniques and search for new REs but also for new structural variants. Based on the Tübingen cohort of 100 unsolved ADCA families, each index patient will be long-read genome sequenced (Nanopore sequencing). A bioinformatics algorithm will be developed and trained on an identically sequenced positive control cohort of ADCA patients with known REs and a control cohort. For the segregation analysis of possible new REs and for evaluation in further cohorts we will apply a new NGS method, which uses the CRISPR/Cas9 system to enrich regions that are difficult to amplify. The "no-amplification targeted sequencing" protocol already available from PacBio makes it possible for the first time to sequence REs with base level resolution using NGS technology in a continuous and economical way. Based on this and similar techniques, we expect rapid progress in the study of repeat-expansion diseases over the next few years, similar to the progress that has followed the introduction of short-read NGS techniques for conventional variants. This project will therefore not only advance the basic research of ADCAs regarding aetiology, pathogenesis and diagnostics, but also contribute to the advancement of current NGS techniques and the associated bioinformatics.
long-read sequencing
CRISPR targeted sequencing
repeat expansions

Involved staff


University Department of Neurology
Hospitals and clinical institutes, Faculty of Medicine
Faculty of Medicine
University of Tübingen
Institute for Bioinformatics and Medical Informatics (IBMI)
Interfaculty Institutes

Contact persons

University Department of Neurology
Hospitals and clinical institutes, Faculty of Medicine

Local organizational units

Department of Neurology with Focus on Neurodegenerative Disorders
University Department of Neurology
Hospitals and clinical institutes, Faculty of Medicine
Hertie Institute for Clinical Brain Research (HIH)
Non-clinical institutes
Faculty of Medicine


Bonn, Nordrhein-Westfalen, Germany

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