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

chr4:39350045-39350103

hg38

chr4:39348425-39348483

t2t

chr4:39318078-39318136

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 al. 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 controls⁶. Length appears to impact age of onset and disease severity, with particular impact from the smaller allele⁷.

Mechanism

LoF

LoF; exact mechanism unknown⁸.

Year

2019⁹

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 · 2024-09-30

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

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

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

pmid:38627134

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)

Spectrum disorder of RFC1 expansions/CANVAS: Clinical and electrophysiological characterization of a group of 31 patients.

Elena,Lainez, Daniel,Sánchez-Tejerina, Paula,Fernández Alvarez, Margarida,Gratacòs-Viñola, José Luis,Seoane, Daniela Isabel,Santa-Cruz, Lena,Verdaguer, Raúl,Juntas, Arnau,Llauradó, Javier,Sotoca, Maria,Salvado, Elena,García Arumi, Núria,Raguer

Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology · 2024-12-19

pmid:39721397

Screening for SCA27B, CANVAS and other repeat expansion disorders in Greek patients with late-onset cerebellar ataxia suggests a need to update current diagnostic algorithms.

Georgios,Koutsis, Chrisoula,Kartanou, Zoi,Kontogeorgiou, Chrysoula,Koniari, Alexandros,Mitrousias, David,Pellerin, Marie-Jose,Dicaire, Pablo,Iruzubieta, Matt C,Danzi, Konstantinos,Athanassopoulos, Nikolaos,Ragazos, Maria,Stamelou, Michail,Rentzos, Evangelos,Anagnostou, Stephan,Zuchner, Bernard,Brais, Henry,Houlden, Marios,Panas, Leonidas,Stefanis, Georgia,Karadima

Journal of the neurological sciences · 2024-11-15

pmid:39571249

Elucidating the pathobiology of Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS) with its expanded RNA structure formation and proteinopathy.

Krishna,Singh, Sakshi,Shukla, Uma,Shankar, Neha,Jain, Rishav,Nag, Kumari Aditi,Pramod, Amit,Kumar

Scientific reports · 2024-11-14

pmid:39543176

Early Peripheral Nerve Involvement at the Time of Coughing in Patients With

Simon,Frachet, Pauline,Chazelas, Laurent,Magy, Pascal,Cintas, Danielle,Brouquières, Pierre,Girardie, Louise,Espagno, Boris,Melloni, Laurent,Guilleminault, Anne-Sophie,Lia

Neurology. Genetics · 2024-07-19

pmid:39507594

Case report: Neuroacanthocytosis associated with novel variants in the

Martin,Paucar, Josephine,Wincent, Charlotta,Rubin, Kevin,Peikert, Josefin,Kyhle, Stellan,Hertegård, Riita,Möller, Soheir,Beshara, Per,Svenningsson

Frontiers in neuroscience · 2024-10-02

pmid:39416949

Characterizing tandem repeat complexities across long-read sequencing platforms with TREAT and

Niccoló,Tesi, Alex,Salazar, Yaran,Zhang, Sven,van der Lee, Marc,Hulsman, Lydian,Knoop, Sanduni,Wijesekera, Jana,Krizova, Anne-Fleur,Schneider, Maartje,Pennings, Kristel,Sleegers, Erik-Jan,Kamsteeg, Marcel,Reinders, Henne,Holstege

Genome research · 2024-11-20

pmid:39406499

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): a family with five affected sibs from Turkey.

Figen,Gökçay, Gülcan Neşem,Baskan, Irmak,Şahbaz, Müge Kovancılar,Koç, A Nazlı,Başak, Nese,Celebisoy

BMC neurology · 2024-09-28

pmid:39342186

Electrophysiological features of the peripheral neuropathy in patients with pathologic biallelic RFC1 repeat expansions.

Claudia,Calezis, Nathalie,Bonello-Palot, Annie,Verschueren, Jean-Philippe,Azulay, Etienne,Fortanier, Aude-Marie,Grapperon, Ludivine,Kouton, Julien,Gallard, Emmanuelle,Salort-Campana, Shahram,Attarian, Emilien,Delmont

Muscle & nerve · 2024-09-17

pmid:39286915

AAGGG repeat expansions trigger

Connor J,Maltby, Amy,Krans, Samantha J,Grudzien, Yomira,Palacios, Jessica,Muiños, Andrea,Suárez, Melissa,Asher, Sydney,Willey, Kinsey,Van Deynze, Camille,Mumm, Alan P,Boyle, Andrea,Cortese, Alain,Ndayisaba, Vikram,Khurana, Sami J,Barmada, Anke A,Dijkstra, Peter K,Todd

Science advances · 2024-09-04

pmid:39231235