Biallelic Intronic AAGGG Expansion of RFC1 is Related to Multiple System Atrophy

Linlin Wan, Zhao Chen, Na Wan, Mingjie Liu, Jin Xue, Hongsheng Chen, Youming Zhang, Yun Peng, Zhichao Tang, Yiqing Gong, Hongyu Yuan, Shang Wang, Qi Deng, Xuan Hou, Chunrong Wang, Huirong Peng, Yuting Shi, Linliu Peng, Lijing Lei, Ranhui DuanKun Xia, Rong Qiu, Lu Shen, Beisha Tang, Tetsuo Ashizawa, Hong Jiang

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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 ~92% of cases. This study aimed to examine whether the pentanucleotide repeat (PNR) was related to multiple system atrophy (MSA), which shares a spectrum of symptoms with CANVAS. Methods: In this study, we screened the pathogenic (AAGGG)exp repeat and 5 other PNRs in 104 Chinese 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 polymerase chain reaction (PCR), repeat-primed PCR (RP-PCR), Sanger sequencing, and Southern blot. Comprehensive clinical assessments were conducted, including neurological examination, neuroimaging, nerve electrophysiology, and examination of vestibular function. Results: We identified biallelic (AAGGG)exp in 1 SAOA patient and 3 MSA patients. Additionally, 1 MSA patient had the (AAGGG)exp/(AAAGG)exp genotype with uncertain pathogenicity. We also described the carrier frequency for different PNRs in our cohorts. 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 as CANVAS, which is crucial for re-evaluating the current CANVAS and MSA diagnostic criteria. ANN NEUROL 2020;88:1132–1143.

Original languageEnglish (US)
Pages (from-to)1132-1143
Number of pages12
JournalAnnals of Neurology
Issue number6
StatePublished - Dec 2020

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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