Overview of repeats
It has been recently found by Cortese and colleagues (2019, 2020) that patients with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) also carry a different repeat unit in their RFC1 gene. The reference region with 11 AAAAG repeats was replaced with biallelic variable number of AAGGG repeats. The number of repeats ranged from around 400 repeats to 2750 (Cortese et al., 2020; Cortese et al., 2019).
In one of these research (Cortese et al., 2019), the locus in healthy controls was determined to be highly polymorphic. After analysing 608 controls, they determined that 75% of them have the reference (AAAAG)11 allele and 13% carried an expanded (15-200 repeats) version of the same repeat. In 8% of cases there was an expansion (400-1000 repeats) of another (AAAGG) motif. Finally, four individuals had expansions in the range of 40-1000 repeats of the pathogenic (AAGGG) motif, which, however, was in the heterozygous state and therefore not pathogenic. In addition, some healthy individuals also had biallelic expansions of different repeat unit combinations, either (AAAAG)exp/(AAAGG)exp, (AAAAG)exp/(AAGGG)exp or (AAAGG)exp/(AAGGG)exp, demonstrating that only biallelic expansions of AAGGG are disease-causing (Cortese et al., 2019).
Biallelic expansions of another motif, ACAGG, has been found in two Asia-Pacific CANVAS families (approximately 1015 repeats) (Scriba et al., 2020) and in one affected Japanese individual (Tsuchiya et al., 2020).