CANVAS RFC1

Sensory disturbances, imbalance, oscillopsia, chronic dry cough, dysarthria and dysphagia¹; Late-onset ataxia, sensory neuropathy, vestibular areflexia syndrome².

Prevalence

Carrier frequency in European is 0.7-4% and in Chinese Han population is 2.24%; estimated prevalence of 1/20,000 to 1/625³. Many cases are likely not diagnosed due to heterogeneous presentation⁴. 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 Australia³.

Age of Onset Details

Typical: 36-52; Range: 19-76³.

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 phenotype³. Pathogenic expansions (ranging from 400-2750 pathogenic motifs) may be flanked by other motifs³. For example, (AAAGG)10-25(AAGGG)exp(AAAGG)4-6⁵. Motif heterogeneity is common in unaffected individuals³, and motif associations are described by Delforge et al⁶. 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 controls⁷. Length appears to impact age of onset and disease severity, with particular impact from the smaller allele⁸. Phenotypic spectrum may include Parkinsonism⁹and chronic cough¹⁰.

Mechanism

LoF

LoF; exact mechanism unknown¹¹.

Year

2019¹²

Location in Gene

Intron 2

Gene Strand

Alleles

Ref. Motif

AAAAG

Benign (ref.)

AAAAG, AAAGG, AAGAG, AAAGGG

Benign (gene)

CTTTT, CCTTT, CTCTT, CCCTTT

Pathogenic (ref.)

AAGGG, ACAGG, AGGGC, AAGGC, AGAGG

Pathogenic (gene)

CCCTT, CCTGT, CCCTG, CCTTG, CCTCT

Unknown (ref.)

AAAAA, AAAAC, AACGG, AAGAC, AAGGT, AGAAC, AGGGG, GAAAC, GGGAC, GTGAG, AAAAGA, AAAGGA, GGAAAG

Unknown (gene)

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

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

RFC1 CANVAS / Spectrum Disorder

Andrea,Cortese, Mary M.,Reilly, Henry,Houlden

GeneReviews® · 1993-01-01

genereviews: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

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)

Video head impulse test differentiates RFC1-CANVAS, FGF14-SCA27B, and idiopathic late-onset cerebellar ataxias.

Leonardo E,Ariello, Daniel R,Gold, Jennifer L,Millar, Michael C,Schubert, Weiyi,Mu, Liana,Rosenthal, David P W,Rastall

Journal of neurology · 2025-10-07

pmid:41055766

Repeat-associated ataxias in a German patient cohort analysed by targeted parallel long-read sequencing.

Hannes,Erdmann, Annalisa,Schaub, Morghan C,Lucas, Veronika,Scholz, Anna,Benet-Pages, Kerstin,Becker, Christine,Dineiger, Veronika,Mayer, Inga,van Buren, Eva,Breithausen, Karl,Akbari, Isabell,Cordts, Mayra,Sauer, Christine,Schneider, Rosanna,Krakowsky, Franziska,Schnabel, Konstanze,Dunker, Lena,Fabritius, Johannes,Gerb, Denis,Grabova, Ken,Möhwald, Marius,Näher, Karoline,Steinmetz, Franziska,Thiessen, Alexander,Jäck, Christiane,Schneider-Gold, Simone,Zittel, Christina,Petersen, Isolde,Schreyer, Larissa,Mämecke, Sibylle,Wilfling, Gilbert,Wunderlich, David,Brenner, Yorck,Hellenbroich, Kirsten,Muhle, Tessa,Huchtemann, Inga,Claus, Thomas,Klopstock, Michael,Strupp, Johannes,Levin, Günter,Höglinger, Doreen,Huppert, Sandra,Becker-Bense, Filipp,Filippopulos, Fabian,Kilpert, Elsa,Leitão, Sabine,Kaya, Christel,Depienne, Florian,Schöberl, Teresa,Neuhann, Elke,Holinski-Feder, Andreas,Zwergal, Angela,Abicht

Brain : a journal of neurology · 2025-09-03

pmid:40898875

Long-read sequencing identifies

Fulya,Akçimen, Kensuke,Daida, Lara M,Lange, Abraham,Moller, Abigail,Miano-Burkhardt, Laksh,Malik, Kimberly,Paquette, Pilar Alvarez,Jerez, Jackson,Mingle, Breeana,Baker, Melissa,Meredith, Cedric,Kouam, Paige,Jarreau, Androo,Markham, Jessica,Anderson, Miten,Jain, Mark,Chaisson, Mark,Cookson, Bradford,Casey, Hirotaka,Iwaki, Sara,Bandres-Ciga, Paula,Saffie-Awad, Mike,Nalls, Zih-Hua,Fang, Andrew B,Singleton, Cornelis,Blauwendraat, Kimberley J,Billingsley

medRxiv : the preprint server for health sciences · 2025-08-19

pmid:40894141

Prevalence of intronic repeat expansions in the RFC1 gene in Polish patients with cerebellar syndrome.

Tomczuk,Filip, Ziora-Jakutowicz,Karolina, Dominik,Natalia, Houlden,Henry, Cortese,Andrea, Rutkowska,Karolina, Pollak,Agnieszka, Ploski,Rafal, Janik,Piotr, Elert-Dobkowska,Ewelina, Sulek,Anna

Journal of applied genetics · 2025-08-13

pmid:40802152

Non-coding repeat analyses in patients with Parkinson's disease.

Makito,Hirano, Makoto,Samukawa, Satoko,Miyatake, Yuko,Yamagishi, Chiharu,Isono, Rino,Yoshikawa, Kazumasa,Saigoh, Atsushi,Terayama, Yuji,Higashimoto, Eriko,Koshimizu, Takeshi,Mizuguchi, Kanako,Fujii, Yoshiyuki,Mitsui, Naomichi,Matsumoto, Yoshitaka,Nagai

Frontiers in neurology · 2025-07-22

pmid:40765612

Late-onset cerebellar ataxia in three European patients with repeat expansions in RFC1 and FGF14: a case series.

Armand,Hocquel, David,Pellerin, Jean Loup,Méreaux, Vincent,Huin, Marios,Hadjivassiliou, Guillemette,Clément, Felipe,Villa, Salomé,Puisieux, Solène,Frismand, Marion,Wandzel, Virginie,Roth, Anna,Wissocq, Thomas,Wirth, Matt C,Danzi, Isabelle,Quadrio, Stephan,Zuchner, Laetitia,Lambert, Fanny,Mochel, Matthis,Synofzik, Mathieu,Anheim, Henry,Houlden, Alexis,Brice, Carine,Pourié, Bernard,Brais, Céline,Bonnet, Alexandra,Durr, Mathilde,Renaud

Journal of neurology · 2025-07-10

pmid:40637932

RFC1 regulates the expansion of neural progenitors in the developing zebrafish cerebellum.

Fanny,Nobilleau, Sébastien,Audet, Alexandra,da Silva Babinet, Sanaa,Tork, Charlotte,Zaouter, Meijiang,Liao, Nicolas,Pilon, Martine,Tétreault, Shunmoogum A,Patten, Éric,Samarut

Nature communications · 2025-07-01

pmid:40595562

Feasibility of long-read sequencing to identify molecular alterations in an Indonesian cohort of locally advanced to advanced nasopharyngeal cancer.

,Handoko, Marlinda,Adham, Lisnawati,Rachmadi, Demak Lumban,Tobing, ,Asmarinah, ,Fadilah, Wei,Dai, Anne Wing Mui,Lee, Soehartati A,Gondhowiardjo

Scientific reports · 2025-07-01

pmid:40594369

Diagnostic yield and limitations of whole-genome sequencing for hereditary cerebellar ataxia.

Wai Yan,Yau, Roisin,Sullivan, Emer,O'Connor, David,Pellerin, Michael H,Parkinson, Paola,Giunti, Marie-Josée,Dicaire, Matt C,Danzi, Stephan,Züchner, Bernard,Brais, Nicholas W,Wood, Henry,Houlden, Jana,Vandrovcova

Brain communications · 2025-05-17

pmid:40488180