{Reference Type}: Journal Article
{Title}: RFC1 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology.
{Author}: Benkirane M;Da Cunha D;Marelli C;Larrieu L;Renaud M;Varilh J;Pointaux M;Baux D;Ardouin O;Vangoethem C;Taulan M;Daumas Duport B;Bergougnoux A;Corbillé AG;Cossée M;Juntas Morales R;Tuffery-Giraud S;Koenig M;Isidor B;Vincent MC;
{Journal}: Brain
{Volume}: 145
{Issue}: 11
{Year}: 11 2022 21
{Factor}: 15.255
{DOI}: 10.1093/brain/awac280
{Abstract}: Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is an inherited late-onset neurological disease caused by bi-allelic AAGGG pentanucleotide expansions within intron 2 of RFC1. Despite extensive studies, the pathophysiological mechanism of these intronic expansions remains elusive. We screened by clinical exome sequencing two unrelated patients presenting with late-onset ataxia. A repeat-primer polymerase chain reaction was used for RFC1 AAGGG intronic expansion identification. RFC1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction. We identified the first two CANVAS affected patients who are compound heterozygous for RFC1 truncating variants (p.Arg388* and c.575delA, respectively) and a pathological AAGGG expansion. RFC1 expression studies in whole blood showed a significant reduction of RFC1 mRNA for both patients compared to three patients with bi-allelic RFC1 expansions. In conclusion, this observation provides clues that suggest bi-allelic RFC1 conditional loss-of-function as the cause of the disease.