Sensory disturbances, imbalance, oscillopsia, chronic dry cough, dysarthria and dysphagia¹; Late-onset ataxia, sensory neuropathy, vestibular areflexia syndrome^2,3. This expansion has been implicated in the genetic etiology of Parkinson's disease⁴.

Prevalence

Carrier frequency in Europeans is 0.7-4% and in Chinese Han population is 2.24%; estimated prevalence of 1/20,000 to 1/625⁵. Many cases are likely not diagnosed due to heterogeneous presentation⁶. 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 Australia⁵.

Age of Onset

Typical: 36-52; Range: 19-76⁵.

HPO Terms

HP:0000364 Hearing abnormality HP:0000407 Sensorineural hearing impairment HP:0000639 Nystagmus HP:0000640 Gaze-evoked nystagmus HP:0000648 Optic atrophy HP:0000750 Delayed speech and language development HP:0001151 Impaired horizontal smooth pursuit HP:0001152 Saccadic smooth pursuit interruptions HP:0001251 Ataxia HP:0001260 Dysarthria HP:0001265 Hyporeflexia HP:0001272 Cerebellar atrophy HP:0001284 Areflexia HP:0001310 Dysmetria HP:0002066 Gait ataxia HP:0002070 Limb ataxia HP:0002073 Progressive cerebellar ataxia HP:0002075 Dysdiadochokinesis HP:0002080 Intention tremor HP:0002172 Postural instability HP:0002403 Positive Romberg sign HP:0002460 Distal muscle weakness HP:0002494 Abnormal rapid eye movement sleep HP:0002495 Impaired vibratory sensation HP:0002828 Multiple joint contractures HP:0003438 Absent Achilles reflex HP:0003447 Axonal loss HP:0003487 Babinski sign HP:0006855 Cerebellar vermis atrophy HP:0007108 Demyelinating peripheral neuropathy HP:0007141 Sensorimotor neuropathy HP:0007230 Decreased distal sensory nerve action potential HP:0007328 Impaired pain sensation HP:0008568 Vestibular areflexia HP:0009830 Peripheral neuropathy HP:0010545 Downbeat nystagmus HP:0012332 Abnormal autonomic nervous system physiology HP:0012735 Cough

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 phenotype⁵. Pathogenic expansions (ranging from 400-2750 pathogenic motifs) may be flanked by other motifs⁵. For example, (AAAGG)10-25(AAGGG)exp(AAAGG)4-6⁷. Motif heterogeneity is common in unaffected individuals⁵, and motif associations are described by Delforge et al.⁸. 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 controls⁹. Length appears to impact age of onset and disease severity, with particular impact from the smaller allele¹⁰. Phenotypic spectrum may include Parkinsonism¹¹, chronic cough¹², idiopathic sensory neuropathy, small fiber neuropathy, and sensorimotor neuropathy¹³. DNA mismatch repair variants may modify penetrance: a polygenic score built from Huntington's disease somatic expansion modifiers was elevated in biallelic AAGGG individuals with ataxia and/or neuropathy versus controls, but not in asymptomatic biallelic carriers¹⁴. The MSH3-tagging variant rs245100 was the main contributor and the only significant variant on its own¹⁴.

Mechanism

LoF

LoF; exact mechanism unknown¹⁵. Simple LoF is contested as RFC1 mRNA, protein, and splicing are normal in biallelic-expansion patient tissue and iPSC-derived neurons^16,17.

Detection

Short-read genotyping substantially over-calls biallelic AAGGG status, with a false positive rate near 50% even when requiring ≥55 repeats on both alleles¹⁴. Expansions are suggested by flanking PCR failure and a pathogenic RP-PCR sawtooth pattern, but biallelic confirmation and sizing rely on Southern blotting⁵. Long-read sequencing or optical genome mapping are useful for resolving this variable, complex motif structure^18,9.

Year

2019¹⁹

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, CAGGG

Pathogen. (gene)

CCCTT, CCTGT, CCTTT, CCCTG

Unknown (ref.)

AAAAA, AAAAC, AACGG, ACAAG, AAGGT, AGGGG, AAGAG, AAAAGG, AAACG, AACAG, GAGGT, ACGGG, AAAAAG, CAAGG

Unknown (gene)

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

Interruption (ref.)

–

Interrup. (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

Bi- and Mono-Allelic RFC1 Expansion in a North American Cohort With Idiopathic Axonal Neuropathy.

Amro M,Stino, Lavanya,Muthukumar, Evan L,Reynolds, Peter,Todd, Sinem,Ovunc, Sheng Chih,Jin, Zitian,Tang, Simone,Thomas, Ahmet,Höke, Brian C,Callaghan

Annals of clinical and translational neurology · 2026-07-05

pmid:42402724

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

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

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

DNA Repair Pathway Variants Are Enriched in Individuals with Biallelic AAGGG CANVAS and RFC1-Related Disease.

Xuemin,Wang, Liam G,Fearnley, Kayli C,Davies, Penny,Snell, Stuart,Lee, Victoria E,Jackson, Justin,Read, Michael,Milton, Ian H,Harding, Martin B,Delatycki, David J,Szmulewicz, Paul J,Lockhart, Melanie,Bahlo, Haloom,Rafehi

Movement disorders : official journal of the Movement Disorder Society · 2026-07-19

pmid:42473260

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

Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia.

Andrea,Cortese, Roberto,Simone, Roisin,Sullivan, Jana,Vandrovcova, Huma,Tariq, Wai Yan,Yau, Jack,Humphrey, Zane,Jaunmuktane, Prasanth,Sivakumar, James,Polke, Muhammad,Ilyas, Eloise,Tribollet, Pedro J,Tomaselli, Grazia,Devigili, Ilaria,Callegari, Maurizio,Versino, Vincenzo,Salpietro, Stephanie,Efthymiou, Diego,Kaski, Nick W,Wood, Nadja S,Andrade, Elena,Buglo, Adriana,Rebelo, Alexander M,Rossor, Adolfo,Bronstein, Pietro,Fratta, Wilson J,Marques, Stephan,Züchner, Mary M,Reilly, Henry,Houlden

Nature genetics · 2019-03-29

pmid:30926972

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

Optical Genome Mapping Enables Detection and Accurate Sizing of

Stefano,Facchini, Natalia,Dominik, Arianna,Manini, Stephanie,Efthymiou, Riccardo,Currò, Bianca,Rugginini, Elisa,Vegezzi, Ilaria,Quartesan, Benedetta,Perrone, Shahedah Koya,Kutty, Valentina,Galassi Deforie, Ricardo P,Schnekenberg, Elena,Abati, Anna,Pichiecchio, Enza Maria,Valente, Cristina,Tassorelli, Mary M,Reilly, Henry,Houlden, Enrico,Bugiardini, Andrea,Cortese

Biomolecules · 2023-10-19

pmid:37892228

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)

DNA Repair Pathway Variants Are Enriched in Individuals with Biallelic AAGGG CANVAS and RFC1-Related Disease.

Movement disorders : official journal of the Movement Disorder Society · 2026-07-19

pmid:42473260

Bi- and Mono-Allelic RFC1 Expansion in a North American Cohort With Idiopathic Axonal Neuropathy.

Amro M,Stino, Lavanya,Muthukumar, Evan L,Reynolds, Peter,Todd, Sinem,Ovunc, Sheng Chih,Jin, Zitian,Tang, Simone,Thomas, Ahmet,Höke, Brian C,Callaghan

Annals of clinical and translational neurology · 2026-07-05

pmid:42402724

Phenotype and Genetics of Spinocerebellar Ataxia Type 27B: Novel Movement-disorder Features, Cognitive Impairment, and Repeat Expansion Findings.

Ronak,Rashedi, Franca,Peemöller, Hannes,Erdmann, Mathias,Gelderblom, Ute,Hidding, Christos,Ganos, Robert,Chen, Angela,Abicht, Simone,Zittel

Cerebellum (London, England) · 2026-06-29

pmid:42371259

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

Locus CANVAS RFC1

Disease

Locus

Alleles

gnomAD

References

Additional Literature