RFC1 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology

• DOI: 10.1093/brain/awac280
• Publication Date: 2022-07-27T04:19:24Z
• Authors: Mehdi Benkirane; Dylan Da Cunha; Cecilia Marelli; Lise Larrieu; Mathilde Renaud; Jessica Varilh; Morgane Pointaux; David Baux; Olivier Ardouin; Charles Vangoethem; Magali Taulan; Benjamin Daumas D...; Anne Bergougnoux; Anne-Gaelle Corbillé; Mireille Cossée; Raul Juntas Morales; Sylvie Tuffery-Gi...; Michel Koenig; Bertrand Isidor; Marie-Claire Vincent
• Keywords: 03 medical and health sciences; 0302 clinical medicine; Cerebellar Ataxia; Reflex, Abnormal; Bilateral Vestibulopathy; Humans; Peripheral Nervous System Diseases; RNA, Messenger; Syndrome; Replication Protein C; 3. Good health

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.