Two RFC1 splicing variants in CANVAS.

Abstract

We read with great interest the original article ‘RFC1 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology’ by Benkirane et al.1 Biallelic RFC1 (AAGGG)n expansions are responsible for cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), a frequent cause of late-onset ataxia, with sporadic or autosomal recessive inheritance.2 Since their discovery, other pathogenic pentanucleotide motifs have been reported in the literature.3-5 The authors reported two cases of heterozygous compound truncating variants of RFC1 in two patients with CANVAS. They were null variants (one frameshift and one nonsense variant) and were associated with a classical RFC1 (AAGGG)n intronic expansion in trans. For the first time, Benkirane et al.1 succeeded in advancing our understanding of the pathophysiology of CANVAS, which, until now, has remained elusive. The authors showed a decrease in RFC1 mRNA levels in the patients’ blood, supporting the hypothesis of a loss-of-function of the gene as the cause of the disease. Here, we report genetic and clinical data from two additional unrelated families with heterozygous compound expansions in RFC1 and loss-of-function pathogenic variants.