Pure frontotemporal dementia, pure amyotrophic lateral sclerosis or combination of the two¹. Nominal associations with risk of Parkinson's have also been reported². May present as non-Huntington chorea in rare cases³.

Prevalence

The expansion of a hexanucleotide repeat GGGGCC in C9orf72 is the most common known cause of ALS accounting for ~ 40% familial cases and ~ 7% sporadic cases in the European population; overall ALS incidence is 1-2/100,000 person-years, point prevalence is 3-5/100,000 (Europe/US); lifetime risk is 1 in 300⁴. Related individuals to patients with C9orf72-ALS appear at an increased risk of disease regardless of carrier status^5,6. C9orf72-FTD is estimated to be 0.04-134:100,000⁷, and by our estimates 0.65-1.56/100,000 for C9orf72-ALS. The expansion has been found across ethnicities/ancestries, with population-dependent prevalence, highest in those with northern European ancestry⁷.

Age of Onset

Typical: 50-64; Range: 20-91⁷.

HPO Terms

–

Association

MendelianRisk

Locus

hg19 chr9:27573482-27573544

hg38 chr9:27573484-27573546

t2t chr9:27584063-27584155

Details

FTD and ALS form a clinical spectrum^8,9. The clinical ranges of the C9orf72 locus remain ambiguous¹⁰¹¹: most healthy controls have alleles up to 24 repeats¹²yet 24-30 repeats are associated with ALS⁴and while 60 repeats is frequently used as a threshold for uncertain alleles, the exact threshold of pathogenicity remains unclear^7,13. Repeats of 80 motifs and lower appear to have delayed onset for any phenotype¹². >250 repeats are associated with a full FTD/ALS disease state¹⁴, but pathogenic alleles can range from 30 to more than 4000 repeats^13,15. Somatic C9orf72 repeat expansions may emerge de novo in CNS tissue from alleles below the pathogenic range, potentially contributing to sporadic ALS/FTD¹⁶. Penetrance appears to also be age-dependent, with environmental factors and specific phenotypes associated with sex and age at onset¹⁷. Methylation appears to increase with expansion length and age¹⁵, and C9orf72 promoter hypermethylation has been observed in expansion carriers¹⁸. ALS caused by repeat expansions in C9orf72 generally has an earlier disease onset and faster progression than other ALS presentations¹⁹. C9orf72 expansions have been associated with reduced thalamic volume in undiagnosed carriers, and plasma neurofilament light chain has an approximately linear association with repeat count and motor neuron disease risk^11,20. Pathogenic C9orf72 repeat expansions have also been identified in ambiguous late onset behavioral or psychiatric like presentations including executive deficits, apathy, and stereotyped behavior²¹.

Mechanism

Ambiguous

The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA/DNA hybrids (R-loops). The structural polymorphism causes a repeat length-dependent accumulation of transcripts aborted in the HRE region²². Additional mechanisms theorized include protein loss-of-function and RNA gain-of-function²³. Multiple cell types in the prefrontal cortex, including oligodendrocytes, microglia, astrocytes, and neurons, appear impacted during pathogenesis²⁴. Drosophila model-system evidence suggests that RAN translated poly(GR) may contribute to toxicity by activating the integrated stress response through eIF2α phosphorylation and promoting stress granule accumulation²⁵. C9orf72 repeat expansions are associated with reduced C9orf72 expression in multiple ALS tissues and altered splicing of the exon 1a isoform²⁶. Reduced C9orf72 expression has also been observed in peripheral blood immune cells from C9orf72-associated ALS, with C9-ALS showing distinct monocyte activation signatures. In ALS spinal cord, activated myeloid cells expressing complement, lipid-processing, and phagocytic genes occur in regions with motor neuron loss and TDP-43 pathology²⁷.

Detection

Bidirectional RP-PCR is typically used for detection [@pmid:21944778]. Large pathogenic expansions are difficult to size exactly by PCR, so Southern blot is used to better estimate size [@pmid:23566336], while long-read sequencing provides direct sizing and sequence characterization [@pmid:30126445].

Year

2011²⁸

Location in Gene

Intron 1 or 5' UTR depending on transcript

Gene Strand

Alleles

Ref. Motif

GGCCCC

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

GGCCCC

Pathogenic (gene)

CCGGGG

Unknown (ref.)

–

Unknown (gene)

–

Interruption (ref.)

–

Interruption (gene)

–

gnomAD

References

Direct supporting references for info on this page.

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Practical neurology · 2025-05-15

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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

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Unraveling the genetic architecture of non-Huntington chorea: a biobank-scale study of rare variants and repeat expansions.

Fulya,Akçimen, Monica,Diez-Fairen, Ignacio,Alvarez, Victor,Puente, Spencer,Grant, Jorge,Hernandez-Vara, Marzieh,Khani, Mariateresa,Buongiorno, Félix Javier,Jiménez-Jiménez, José A G,Agúndez, Miquel,Aguilar, Esther,Cubo, Jesus,Perez, Javier,Pagonabarraga, Núria,Caballol, Asuncion,Avila, Jinhui,Ding, Elena,García-Martín, Hortensia,Alonso-Navarro, Yaroslau,Compta, Carlos,Cruchaga, Katrin,Beyer, J Raphael,Gibbs, Andrew,Singleton, Sara,Bandres-Ciga, Pau,Pastor

NPJ genomic medicine · 2026-04-09

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C9orf72 intermediate expansions of 24-30 repeats are associated with ALS.

Alfredo,Iacoangeli, Ahmad,Al Khleifat, Ashley R,Jones, William,Sproviero, Aleksey,Shatunov, Sarah,Opie-Martin, Karen E,Morrison, Pamela J,Shaw, Christopher E,Shaw, Isabella,Fogh, Richard J,Dobson, Stephen J,Newhouse, Ammar,Al-Chalabi

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Neurology. Genetics · 2023-12-22

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Personalised penetrance estimation for C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia.

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BMJ neurology open · 2024-09-18

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C9orf72 Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis

Helena,Gossye, Sebastiaan,Engelborghs, Christine,Van Broeckhoven, Julie,Zee

GeneReviews® · 1993-01-01

genereviews:NBK268647

Genome-wide structural variant analysis identifies risk loci for non-Alzheimer's dementias.

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Cell genomics · 2023-05-04

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Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study.

Elisa,Majounie, Alan E,Renton, Kin,Mok, Elise G P,Dopper, Adrian,Waite, Sara,Rollinson, Adriano,Chiò, Gabriella,Restagno, Nayia,Nicolaou, Javier,Simon-Sanchez, John C,van Swieten, Yevgeniya,Abramzon, Janel O,Johnson, Michael,Sendtner, Roger,Pamphlett, Richard W,Orrell, Simon,Mead, Katie C,Sidle, Henry,Houlden, Jonathan D,Rohrer, Karen E,Morrison, Hardev,Pall, Kevin,Talbot, Olaf,Ansorge, Dena G,Hernandez, Sampath,Arepalli, Mario,Sabatelli, Gabriele,Mora, Massimo,Corbo, Fabio,Giannini, Andrea,Calvo, Elisabet,Englund, Giuseppe,Borghero, Gian Luca,Floris, Anne M,Remes, Hannu,Laaksovirta, Leo,McCluskey, John Q,Trojanowski, Vivianna M,Van Deerlin, Gerard D,Schellenberg, Michael A,Nalls, Vivian E,Drory, Chin-Song,Lu, Tu-Hsueh,Yeh, Hiroyuki,Ishiura, Yuji,Takahashi, Shoji,Tsuji, Isabelle,Le Ber, Alexis,Brice, Carsten,Drepper, Nigel,Williams, Janine,Kirby, Pamela,Shaw, John,Hardy, Pentti J,Tienari, Peter,Heutink, Huw R,Morris, Stuart,Pickering-Brown, Bryan J,Traynor

The Lancet. Neurology · 2012-03-09

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stripy:C9ORF72

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Nature · 2026-04-08

pmid:41951733

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pmid:28319737

Analysis of normal

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Amyotrophic lateral sclerosis & frontotemporal degeneration · 2024-01-23

pmid:38099605

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Xueyin,Wang, Karen J,Goodrich, Erin G,Conlon, Jianchao,Gao, Annette H,Erbse, James L,Manley, Thomas R,Cech

RNA (New York, N.Y.) · 2019-05-02

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Targeted long-read sequencing to quantify methylation of the C9orf72 repeat expansion.

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Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit.

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pTDP-43 levels correlate with cell type-specific molecular alterations in the prefrontal cortex of

Hsiao-Lin V,Wang, Jian-Feng,Xiang, Chenyang,Yuan, Austin M,Veire, Tania F,Gendron, Melissa E,Murray, Malú G,Tansey, Jian,Hu, Marla,Gearing, Jonathan D,Glass, Peng,Jin, Victor G,Corces, Zachary T,McEachin

Proceedings of the National Academy of Sciences of the United States of America · 2025-02-25

pmid:39999167

Targeting the integrated stress response or Ataxin-2 alleviates neurodegeneration in PolyGR models of C9orf72 associated frontotemporal dementia and amyotrophic lateral sclerosis.

Nikki S,Harper, Joanne L,Sharpe, Jasmine,Speranza, Ravinder,Gulia, Jeffrey X,Chen, Scott P,Allen, Manpreet S,Atwal, Stuart,Pickering-Brown, Matthew R,Livesey, Craig L,Bennett, Andreas,Prokop, Albert R,La Spada, Ryan J H,West

Acta neuropathologica communications · 2026-05-05

pmid:42087256

The New York Genome Center ALS Consortium resource integrates postmortem tissue transcriptomics and whole genome sequencing to empower biological discovery.

Jack,Humphrey, Ali,Oku, Marta,Byrska-Bishop, Anna O,Basile, Uday S,Evani, André,Corvelo, Alex,Tokolyi, Kailash,Bp, Aline,Réal, Yebin,Kim, Marielle L,Bond, Wayne E,Clarke, Rui,Fu, Heather,Geiger, Sei,Chang, Tatsuhiko,Naito, Beomjin,Jang, Rajeeva,Musunuri, Winston H,Dredge, Rashid,Al-Abri, Benjamin N,Hoover, Dina,Manaa, Jaime,McClintock, Faith P,Singh, Maria H,Pedersen, Alexi,Runnels, Nadia,Propp, Samantha,Fennessey, Hong-Hee,Won, Michael C,Zody, Giuseppe,Narzisi, Nicolas,Robine, Tuuli,Lappalainen, Delphine,Fagegaltier, Gamze,Gürsoy, David A,Knowles, Towfique,Raj, Matthew B,Harms, Hemali,Phatnani

medRxiv : the preprint server for health sciences · 2026-05-04

pmid:42145639

Integrated single-cell and spatial transcriptomic profiling in ALS uncovers peripheral-to-central immune infiltration and reprogramming.

Ziyang,Zhang, Lynn,van Olst, Francesco,Alessandrini, Matthew,Wright, Alex J,Edwards, Jake,Boles, Anait,Nalbandian, Anne V,Forsyth, Nate,Shepard, Thomas,Watson, Evan,Kaspi, Angeli,Mittal, Joshua,Kuruvilla, Natalie,Piehl, Abhirami,Ramakrishnan, Stanley,Appel, Evangelos,Kiskinis, David,Gate

Nature neuroscience · 2026-05-14

pmid:42135512

Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.

Mariely,DeJesus-Hernandez, Ian R,Mackenzie, Bradley F,Boeve, Adam L,Boxer, Matt,Baker, Nicola J,Rutherford, Alexandra M,Nicholson, NiCole A,Finch, Heather,Flynn, Jennifer,Adamson, Naomi,Kouri, Aleksandra,Wojtas, Pheth,Sengdy, Ging-Yuek R,Hsiung, Anna,Karydas, William W,Seeley, Keith A,Josephs, Giovanni,Coppola, Daniel H,Geschwind, Zbigniew K,Wszolek, Howard,Feldman, David S,Knopman, Ronald C,Petersen, Bruce L,Miller, Dennis W,Dickson, Kevin B,Boylan, Neill R,Graff-Radford, Rosa,Rademakers

Neuron · 2011-09-21

pmid:21944778

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)

Multimodal analysis of cell-free DNA identifies epigenetic biomarkers for amyotrophic lateral sclerosis diagnosis and progression.

The Journal of clinical investigation · 2026-06-01

pmid:42222887

Global transcriptional changes across multiple isogenic

Aparna,Sreeram, Desiree M,Baron, Alberto,Brusati, Karly,Stallworth, Jack,Humphrey, John E,Landers

iScience · 2026-05-22

pmid:42221822

Disrupted sleep-wake cycles and circadian rhythms in a

Kendall E,Eby, Braeden R,Shields, Isabella,DelNegro, Sarah,Morley, Pamela A,Snodgrass-Belt, Marla,Tipping

Frontiers in neuroscience · 2026-05-13

pmid:42211284

Immunotherapeutic landscape of amyotrophic lateral sclerosis: A bibliometric analysis of research trends, translational priorities, and collaboration networks (2006-2025).

Ming,Zhang, Wenshuo,Yang, Junxin,Wang, Biqi,Zou, Jialin C,Zheng, Qihui,Wu, Ge,Gao

Human vaccines & immunotherapeutics · 2026-05-20

pmid:42160515