Biallelic intronic AAGGG expansion of RFC1 is related to multiple system atrophy.

OBJECTIVE A recessive biallelic repeat expansion, (AAGGG)exp , in the RFC1 gene has been reported to be a frequent cause of late-onset ataxia. For cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), the recessive biallelic (AAGGG)exp genotype was present in approximately 92% of cases. This study aimed to examine whether the pentanucleotide repeat (PNR) was related to multiple system atrophy (MSA) which shared a spectrum of symptoms with CANVAS. METHODS In this study, we screened the pathogenic (AAGGG)exp repeat and five other PNRs in Chinese 104 sporadic adult-onset ataxia of unknown aetiology (SAOA) patients, 282 MSA patients and 203 unaffected individuals. Multiple molecular genetic tests were used, including long-range PCR, RP-PCR, Sanger sequencing and Southern blot. Comprehensive clinical assessments were conducted including neurological examination, neuroimaging, nerve electrophysiology and vestibular function examination. RESULTS We identified biallelic (AAGGG)exp in one SAOA patient and three MSA patients. Additionally, an MSA patient had the (AAGGG)exp /(AAAGG)exp genotype with uncertain pathogenicity. The carrier frequency for different PNRs in our cohorts was also described. Furthermore, we summarized the distinct phenotypes of affected patients, suggesting that biallelic (AAGGG)exp in RFC1 could be associated with MSA and should be screened routinely in the MSA diagnostic workflow. INTERPRETATION Our results expanded the clinical phenotypic spectrum of RFC1-related disorders and raised the possibility that MSA might share the same genetic background with CANVAS, which was crucial for re-evaluating the current CANVAS and MSA diagnostic criteria. This article is protected by copyright. All rights reserved.