Identification of genetic modifiers of Friedreich’s ataxia

The GAA expansion length associated with Friedreich ataxia (FRDA) correlates with severity of symptoms and inversely with age of onset, particularly for the shorter allele (GAA1), with a prediction of 2.3 years earlier onset for every 100 GAA repeats added to GAA1. However, the GAA repeat size only accounts for between 36% to 56% of the variation in age of onset, and the GAA expansion content has only been investigated for large-scale interruptions. This suggests that other contributory factors, such as non-coding or coding modifying genetic variation, environmental factors, or small repeat sequence interruptions, may influence age of onset and severity. Identifying these factors in FRDA will be important in a number of ways, such as: 1. To define the individual genetic profile of each patient to help determine disease progression, predict clinical problems, and understand allele lengths and age at onset; 2. To stratify patients more effectively for treatment trials; and 3. The modifying molecular pathways identified will certainly improve our understanding of FRDA and may, in themselves, be potential therapeutic targets. This international group collected a large series of FRDA from Europe/South America with DNA and core clinical features. The following aims will be carried out to identify genetic modifying factors in FRDA: A. A genome-wide association study (GWAS) to identify genetic variants associated with (a) FRDA age at onset (AAO), (b) disease progression in FRDA, and (c) investigate the overlap of modifiers associated with other repeat disorders (such as HD and SCAs). This part of the project will be funded by Vertex Pharmaceuticals in a joint project with FARA. Vertex will fund genotyping of FRDA in each FRDA patient at University College London to enable collaboration with colleagues in the United States (Prof David Lynch and colleagues), where Vertex is currently funding SNP genotyping of their FRDA cases (to be completed in 2020) and enable comparison of data. B. Identify biological pathways and gene networks influencing FRDA age at onset and severity. C. Long-read sequencing of the FRDA GAA expansion to assess variation/and repeat changes in the FRDA expansion tract and the 5′ and 3′ flanking regions of the expansion, we will also carry out PacBio long-read sequencing of 400 FRDA patients. The group is keen to be in contact with other research groups and clinical teams that are interested in being part of this study: email h.houlden@ucl.ac.uk