Sensory disturbances, imbalance, oscillopsia, chronic dry cough, dysarthria and dysphagia¹; Late-onset ataxia, sensory neuropathy, vestibular areflexia syndrome². This expansion has been implicated in the genetic etiology of Parkinson's disease³.

Prevalence

Carrier frequency in Europeans is 0.7-4% and in Chinese Han population is 2.24%; estimated prevalence of 1/20,000 to 1/625⁴. Many cases are likely not diagnosed due to heterogeneous presentation⁵. Observed in multiple ethnicities¹; patients diagnosed with European, Chinese Han, and Maori ancestry, as well as found in Japan, Canada, Brazil, the UK, Italy, Germany, and Australia⁴.

Age of Onset

Typical: 36-52; Range: 19-76⁴.

HPO Terms

–

Association

Mendelian

Locus

hg19 chr4:39350044-39350103

hg38 chr4:39348424-39348483

t2t chr4:39318077-39318136

Details

Disease is caused by an insertion of a pathogenic motif, although motif presence is variable and can expand up to 200 repeats without apparently causing a phenotype⁴. Pathogenic expansions (ranging from 400-2750 pathogenic motifs) may be flanked by other motifs⁴. For example, (AAAGG)10-25(AAGGG)exp(AAAGG)4-6⁶. Motif heterogeneity is common in unaffected individuals⁴, and motif associations are described by Delforge et al.⁷. The pathogenic size threshold appears to differ for the AAAGG motif: AAAGG expansions >= 600 repeats have been observed in CANVAS patients (vs 400 with established pathogenic motif AAGGG), while ~100-380 AAAGG repeats were found in unaffected controls⁸. Length appears to impact age of onset and disease severity, with particular impact from the smaller allele⁹. Phenotypic spectrum may include Parkinsonism¹⁰, chronic cough¹¹, idiopathic sensory neuropathy, small fiber neuropathy, and sensorimotor neuropathy¹².

Mechanism

LoF

LoF; exact mechanism unknown¹³.

Detection

Expansions are suggested by flanking PCR failure and a pathogenic RP-PCR sawtooth pattern, but biallelic confirmation and sizing rely on Southern blotting [@genereviews:NBK564656]. Long-read sequencing or optical genome mapping are useful for resolving this variable, complex motif structure [@pmid:37892228; @pmid:37450567].

Year

2019¹⁴

Location in Gene

Intron 2

Gene Strand

Alleles

Ref. Motif

AAAAG

Ranges

Benign (ref.)

AAAAG, AAAGGG

Benign (gene)

CTTTT, CCCTTT

Pathogenic (ref.)

AAGGG, ACAGG, AAAGG, AGGGC

Pathogenic (gene)

CCCTT, CCTGT, CCTTT, CCCTG

Unknown (ref.)

AAAAA, AAAAC, AACGG, AAGAC, AAGGT, AGGGG, AAGAG, AAAAGG, AAACG, AACAG, AGGTG, ACGGG, AAAAAG, AAGGC

Unknown (gene)

TTTTT, GTTTT, CCGTT, CTTGT, ACCTT, CCCCT, CTCTT, CCTTTT, CGTTT, CTGTT, ACCTC, CCCGT, CTTTTT, CCTTG

Interruption (ref.)

–

Interruption (gene)

–

gnomAD

References

Direct supporting references for info on this page.

Neurological disorders caused by novel non-coding repeat expansions: clinical features and differential diagnosis.

Elisa,Vegezzi, Hiroyuki,Ishiura, D Cristopher,Bragg, David,Pellerin, Francesca,Magrinelli, Riccardo,Currò, Stefano,Facchini, Arianna,Tucci, John,Hardy, Nutan,Sharma, Matt C,Danzi, Stephan,Zuchner, Bernard,Brais, Mary M,Reilly, Shoji,Tsuji, Henry,Houlden, Andrea,Cortese

The Lancet. Neurology · 2024-07-01

pmid:38876750

Repeat expansion disorders.

Zhongbo,Chen, Huw R,Morris, James,Polke, Nicholas W,Wood, Sonia,Gandhi, Mina,Ryten, Henry,Houlden, Arianna,Tucci

Practical neurology · 2025-05-15

pmid:39349043

Biallelic RFC1 Expansions Are a Rare Cause of Early-Onset and Familial Parkinson's Disease.

Anja,Kovanda, Lara,Šušmelj, Helena,Jaklič, Tadeja,Lukežič, Aleš,Maver, Igor,Petrovic, Natasa Dragasevic,Miskovic, Marina,Svetel, Valentino,Rački, Vladimira,Vuletič, Ivana,Novakovic, Borut,Peterlin

Clinical genetics · 2025-11-02

pmid:41177915

4genereviews:NBK564656

Pseudodominance in RFC1-Spectrum Disorder.

Grazia Maria Igea,Falcone, Alessandra,Tessa, Ignazio Giuseppe,Arena, Melissa,Barghigiani, Alba,Migliorato, Alex,Incensi, Carmelo,Rodolico, Vincenzo,Donadio, Filippo Maria,Santorelli, Olimpia,Musumeci

Cerebellum (London, England) · 2024-09-04

pmid:39230846

A Māori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele.

Sarah J,Beecroft, Andrea,Cortese, Roisin,Sullivan, Wai Yan,Yau, Zoe,Dyer, Teddy Y,Wu, Eoin,Mulroy, Luciana,Pelosi, Miriam,Rodrigues, Rachael,Taylor, Stuart,Mossman, Ruth,Leadbetter, James,Cleland, Tim,Anderson, Gianina,Ravenscroft, Nigel G,Laing, Henry,Houlden, Mary M,Reilly, Richard H,Roxburgh

Brain : a journal of neurology · 2020-09-01

pmid:32851396

RFC1: Motifs and phenotypes.

V,Delforge, C,Tard, J-B,Davion, K,Dujardin, A,Wissocq, C-M,Dhaenens, E,Mutez, V,Huin

Revue neurologique · 2024-04-15

pmid:38627134

Normal and pathogenic variation of RFC1 repeat expansions: implications for clinical diagnosis.

Natalia,Dominik, Stefania,Magri, Riccardo,Currò, Elena,Abati, Stefano,Facchini, Marinella,Corbetta, Hannah,Macpherson, Daniela,Di Bella, Elisa,Sarto, Igor,Stevanovski, Sanjog R,Chintalaphani, Fulya,Akcimen, Arianna,Manini, Elisa,Vegezzi, Ilaria,Quartesan, Kylie-Ann,Montgomery, Valentina,Pirota, Emmanuele,Crespan, Cecilia,Perini, Glenda Paola,Grupelli, Pedro J,Tomaselli, Wilson,Marques, Joseph,Shaw, James,Polke, Ettore,Salsano, Silvia,Fenu, Davide,Pareyson, Chiara,Pisciotta, George K,Tofaris, Andrea H,Nemeth, John,Ealing, Aleksandar,Radunovic, Seamus,Kearney, Kishore R,Kumar, Steve,Vucic, Marina,Kennerson, Mary M,Reilly, Henry,Houlden, Ira,Deveson, Arianna,Tucci, Franco,Taroni, Andrea,Cortese

Brain : a journal of neurology · 2023-12-01

pmid:37450567

RFC1 CANVAS: genotype phenotype correlations

Curro,Riccardo, Natalia,Dominik, Stojkovic,Tanya, Miller,James, Gosal,David, Hadivassiliou,Marios, Giunti,Paola, Henry,Houlden, Reilly,Mary M, Cortese,Andrea

RFC1 CANVAS: genotype phenotype correlations · 2024-11-01

doi:10.1136/jnnp-2024-ABN.259

Long-read sequencing revealed complex biallelic pentanucleotide repeat expansions in RFC1-related Parkinson's disease.

Peng,Liu, Fan,Zhang, Xinhui,Chen, Xiaosheng,Zheng, Miao,Chen, Zhiru,Lin, Shuqi,Chen, Lebo,Wang, Xinchen,Wang, Nan,Jin, Chenxin,Ying, Fei,Xie, Bo,Wang, Sheng,Wu, Zhidong,Cen, Wei,Luo

NPJ Parkinson's disease · 2025-01-20

pmid:39833204

Repeat expansions in

Barnaby,Hirons, Peter S P,Cho, Katie,Rhatigan, Joe,Shaw, Riccardo,Curro, Bianca,Rugginini, Natalia,Dominik, Richard D,Turner, Ewan,Mackay, James H,Hull, Hisham,Abubakar-Waziri, Harini,Kesavan, Caroline J,Jolley, Robert D,Hadden, Andrea,Cortese, Surinder S,Birring

ERJ open research · 2025-01-13

pmid:39811557

Homozygous RFC1 AAGGG Repeat Expansions Are Common in Idiopathic Peripheral Neuropathy.

Zitian,Tang, Sinem S,Ovunc, Ryo,Iwase, Elle,Mehinovic, Simone,Thomas, Jenna,Ulibarri, Zefan,Li, Dustin,Baldridge, Carlos,Cruchaga, Menghan,Liu, Matt,Johnson, Jeffrey,Milbrandt, Brian,Callaghan, Ahmet,Höke, Peter K,Todd, Sheng Chih,Jin

Annals of neurology · 2026-04-11

pmid:41964406

Sequence composition changes in short tandem repeats: heterogeneity, detection, mechanisms and clinical implications.

Indhu-Shree,Rajan-Babu, Egor,Dolzhenko, Michael A,Eberle, Jan M,Friedman

Nature reviews. Genetics · 2024-03-11

pmid:38467784

Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS.

Haloom,Rafehi, David J,Szmulewicz, Mark F,Bennett, Nara L M,Sobreira, Kate,Pope, Katherine R,Smith, Greta,Gillies, Peter,Diakumis, Egor,Dolzhenko, Michael A,Eberle, María García,Barcina, David P,Breen, Andrew M,Chancellor, Phillip D,Cremer, Martin B,Delatycki, Brent L,Fogel, Anna,Hackett, G Michael,Halmagyi, Solange,Kapetanovic, Anthony,Lang, Stuart,Mossman, Weiyi,Mu, Peter,Patrikios, Susan L,Perlman, Ian,Rosemergy, Elsdon,Storey, Shaun R D,Watson, Michael A,Wilson, David S,Zee, David,Valle, David J,Amor, Melanie,Bahlo, Paul J,Lockhart

American journal of human genetics · 2019-06-20

pmid:31230722

Additional Literature

Additional literature related to this locus.

Raw PubMed search results
(All PubMed results returned by searching for this gene, tandem repeats, and disease, in medline format)

Frequency and phenotype of GAA-FGF14 disease in bilateral vestibulopathy syndromes: insights from repeat expansion carriers, including a case of co-occurrence with RFC1-related CANVAS.

David,Pellerin, Felix,Heindl, Andreas,Traschütz, Pablo,Iruzubieta, Marie-Josée,Dicaire, Stephan,Zuchner, Annette M,Hartmann, Dan,Rujescu, Henry,Houlden, Bernard,Brais, Michael,Strupp, Matthis,Synofzik

Journal of neurology · 2026-05-25

pmid:42178418

Identification of FGF14 GAA Expansions in Polish Patients with Undiagnosed Cerebellar Ataxia - A Preliminary Study.

Marta,Matlawska, Karolina,Ziora-Jakutowicz, Marie-Josee,Dicaire, Joanna,Pera, David,Pellerin, Bernard,Brais, Pablo,Iruzubieta, Ewelina,Elert-Dobkowska, Anna,Sulek

Cerebellum (London, England) · 2026-05-07

pmid:42096001

Genome-wide detection and clinical prioritization of tandem repeat outliers using long-read sequencing.

Sophia B,Gibson, Nikhita,Damaraju, J Gus,Gustafson, Elsa V,Balton, Sirisak,Chanprasert, Ian A,Glass, Martha,Horike-Pyne, Runjun D,Kumar, Kathleen A,Leppig, Chris,Lundberg, Jane,Ranchalis, Elisabeth A,Rosenthal, Andrew K,Solomon, Andrew B,Stergachis, Mark,Wener, Gail P,Jarvik, Elizabeth E,Blue, Katrina M,Dipple, Harriet,Dashnow, Lea M,Starita, Danny E,Miller

medRxiv : the preprint server for health sciences · 2026-05-01

pmid:42094143

Detection of short tandem repeat expansions on a targeted neurological gene panel using STRipy improves the diagnostic rate for ataxias.

Carolin K,Scriba, Chiara,Folland, Michael,Black, Jessica,Baker, Daniel,Abromeit, Samantha,Saw, Mei-Ting,Chiew, Rebecca,Gooding, Nigel G,Laing, Mark R,Davis, Gianina,Ravenscroft

Brain communications · 2026-03-16

pmid:42038259

Targeted neurological screening for RFC1-related disease in unexplained chronic cough.

Vicente,Gajate-García, María,Fenollar-Cortés, Juan Luis,Rodríguez-Hermosa, Marina,Lara-González, Clara,Herrero-Forte, Iván,Muerte-Moreno, Miriam,Calle-Rubio, Alejandro,Horga

Journal of neurology · 2026-03-16

pmid:41840142

Vestibular assessment in definite cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS): A case of siblings study.

Kazunori,Matsuda, Go,Sato, Sho,Takaoka, Yusuke,Osaki, Junya,Fukuda, Miki,Tomura, Seiichiro,Kamimura, Eiji,Kondo, Takahiro,Azuma, Yoshiaki,Kitamura, Yuishin,Izumi, Noriaki,Takeda

Auris, nasus, larynx · 2026-03-03

pmid:41780084

Oculomotor abnormalities in patients with cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) reflect midline cerebellar impairment.

Renana,Storm, Bente,Lübbers, Max,Borsche, Emmelie,Weiss, Astrid,Nümann, Christos,Ganos, Norbert,Brüggemann, Christoph,Helmchen, Andreas,Sprenger

Journal of neurology · 2026-02-14

pmid:41689662

Pentanucleotide guanine-rich WGGGW repeats, including CANVAS AGGGA repeats, form a variety of noncanonical structures.

Jiawei,Wang, Dehui,Qiu, Jun,Zhou, Jean-Louis,Mergny, Patrizia,Alberti

Nucleic acids research · 2026-01-22

pmid:41614301

RFC1 Repeat Expansion in Chronic Cough: Findings From the Korean Chronic Cough Registry.

Kyung Eun,Park, Jiwon,Lee, Jun-Pyo,Choi, Ji-Yoon,Oh, Ha-Kyeong,Won, Hwa Young,Lee, Surinder S,Birring, Heung-Woo,Park, Sang Heon,Cho, Woo-Jung,Song

Allergy, asthma & immunology research · 2026-01-01

pmid:41592538

Locus CANVAS RFC1

Disease

Locus

Alleles

gnomAD

References

Additional Literature