CANVAS RFC1

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 European 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 Details

Typical: 36-52; Range: 19-76⁴.

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 al⁷. 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 Parkinsonism¹⁰and chronic cough¹¹.

Mechanism

LoF

LoF; exact mechanism unknown¹².

Year

2019¹³

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

Pathogenic Genotype (%): % of individuals predicted to be affected based on their genotype

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)

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

Comprehensive phenotyping of RFC1-related disorder: integrating electrophysiological, brain imaging, and otoneurological data in deep phenotyping.

André Aires,Fernandes, Pedro L,Alexandre, Sofia,Vedor, Rita,Figueiredo, Pedro,Marques, Luís,Braz

Arquivos de neuro-psiquiatria · 2025-10-27

pmid:41145152

First Report of Co-Occurring FGF14 (SCA27B) and RFC1 (CANVAS) Repeat Expansions in Two of Three Siblings with Late-Onset Cerebellar Ataxia.

Tasos,Tsokkos, Kyproula,Christodoulou, Christina,Votsi, Anthi,Georghiou, Andrea,Christofides, Astero,Constantinou, Eleni,Zamba-Papanicolaou

Cerebellum (London, England) · 2025-10-21

pmid:41118032

Pseudodominant Inheritance of Biallelic RFC1 Expansions-Revisiting the 3p22-p24 HSN1B Locus.

Bianca R,Grosz, Melina,Ellis, Shuchi,Trivedi, Carolin,Scriba, Marion,Stoll, Danqing,Zhu, Sanjog R,Chintalaphani, Igor,Stevanovski, Andrea,Cortese, Penelope J,Spring, Nigel G,Laing, Ira W,Deveson, Mary M,Reilly, Garth A,Nicholson, Kishore R,Kumar, Steve,Vucic, Marina L,Kennerson

Journal of the peripheral nervous system : JPNS · 2025-12-01

pmid:41084404

Association of Non-Coding Repeat Expansions with Parkinson's Disease Risk: Evidence from a UK Biobank-Based Whole-Genome Sequencing Study.

Zhen,Hu, Qin-Qin,Yan, Jing-Jin,Wan, Yu,Fan, Jun,Liu

Movement disorders : official journal of the Movement Disorder Society · 2025-10-11

pmid:41074692

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