Overview of repeats
Expansions in C9orf72 gene are linked to the amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and is a common cause for ALS, FTD and FTD-ALS diseases, accounting for 11%, 4-29% and 17-28% of cases, respectively (Van Mossevelde et al., 2018). In addition, the frequency is higher for familial cases of the diseases (38% in ALS, 29% in FTD and up to 88% in FTD-ALS) (Van Mossevelde et al., 2018). Repeat expansions have been also detected in patients diagnosed with other neurodegenerative diseases, such as Alzheimer's, Parkinson, and Huntington disease-like disease (Beck et al., 2013; Cacace et al., 2013; Lesage et al., 2013; Woollacott & Mead, 2014).
Normal and pathogenic ranges are not very well defined and varies. In a healthy population, repeats usually range from 1 to 23, whereas 2 repeats is the most common allele (Rutherford et al., 2012), but larger alleles, such as ones with 35 repeats (Simón-Sánchez et al., 2012) or ever over 400 (Beck et al., 2013) have been also observed in healthy individuals. Despite that, the pathogenic range is generally considered above 30 repeats and likely reaching up to thousands of repeats, but the minimum length is not well defined (Woollacott & Mead, 2014). On on hand, it is suggested that alleles between 30-45 should not be considered as pathogenic (Kaivola et al., 2019). On the other hand, a meta-analysis comprising 5071 cases showed significant association between ALS and intermediate C9orf72 repeats of 24 to 30 repeats, suggesting to lower the pathogenic cut-off to at least 24 repets (Iacoangeli et al., 2019). The intermediate range is not well defined, generally considered to have at least 20 repeats, but the effect of such expansion is unknown and alleles are observed in healthy as well as ALS patients with no distribution differences (Iacoangeli et al., 2019).