Although still unproven, one striking predisposition, particularly in repeat expansion disorders such as HD, Friedreich’s ataxia (FA) and C9ORF72-related ALS [119,120,121,122], might arise from the propensity to form R-loops, which are strongly associated with repeat expansion instability, repression and abortion of transcription and elongation and dually with genomic instability and DNA repair [59,123]. The gene discussed is C9orf72; the disease is amyotrophic lateral sclerosis.