Genetic modifiers of the CANVAS (RFC1 expansion) and other recessive repeat expansion disorders

Identifying contributory factors to CANVAS and FRDA such as non-coding or coding modifying genetic variation.

CANVAS is caused by RFC1 expansions and is a frequent cause of inherited ataxia. There are other causes of recessive ataxia, where the most prevalent one is Friedreich ataxia (FRDA) caused by GAA expansions. The RFC1 expansion is an AAGGG but is as yet not known to correlate with age at onset (AAO) or clinical features and the FRDA associated GAA expansion length does correlate with severity of symptoms and inversely with age-of-onset but there are still significant AAO and clinical variability that is unrelated to the expansion size. This suggests that other contributory factors such as non-coding or coding modifying genetic variation exist.

Identifying these factors 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 these disorders and may in themselves be potential therapeutic targets.

Cohorts used CANVAS and FRDA
Funding available? Yes (Ataxia UK & FARA), further application under review
Trial readiness category 1:   basic prerequisites for trial readiness

Contact persons:
Andrea Cortese
Institute of Neurology, University College London, United Kingdom

Henry Houlden
Institute of Neurology, University College London, United Kingdom

Further project partners:
International study with many European, North and South American collaborators.