FTDALS1 C9orf72

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 Details

Typical: 50-64; Range: 20-91⁷.

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 carriers. ALS caused by repeat expansions in C9orf72 generally has an earlier disease onset and faster progression than other ALS presentations¹⁸. 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^11,19. Pathogenic C9orf72 repeat expansions have also been identified in ambiguous late onset behavioral or psychiatric like presentations. Bidirectional RP-PCR is typically used for detection²⁰. Large pathogenic expansions are difficult to size exactly by PCR, so Southern blot provides approximate size²¹, while long read sequencing provides direct sizing and sequence characterization²².

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 region²³. Addiitonal mechanisms theorized include protein loss of function and RNA gain of function²⁴. Multiple cell types in the prefrontal cortex, including oligodendrocytes, microglia, astrocytes, and neurons, appear impacted during pathogenesis²⁵. 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 accumulation²⁶. C9orf72 repeat expansions are associated with reduced C9orf72 expression in multiple ALS tissues and altered splicing of the exon 1a isoform. 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 pathology.

Year

2011²⁰

Location in Gene

Intron 1 or 5' UTR depending on transcript

Gene Strand

Alleles

Ref. Motif

GGCCCC

Pathogenic (ref.)

GGCCCC

Pathogenic (gene)

CCGGGG

gnomAD

References

Direct supporting references for info on this page.

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

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

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

Acta neuropathologica communications · 2019-07-17

pmid:31315673

Marie,Ryan, Mark A,Doherty, Ahmad,Al Khleifat, Emmet,Costello, Jennifer C,Hengeveld, Mark,Heverin, Ammar,Al-Chalabi, Russell L,Mclaughlin, Orla,Hardiman

Neurology. Genetics · 2023-12-22

pmid:38149039

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

Andrew G L,Douglas, Alexander G,Thompson, Martin R,Turner, Kevin,Talbot

BMJ neurology open · 2024-09-18

pmid:39315390

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.

Karri,Kaivola, Ruth,Chia, Jinhui,Ding, Memoona,Rasheed, Masashi,Fujita, Vilas,Menon, Ronald L,Walton, Ryan L,Collins, Kimberley,Billingsley, Harrison,Brand, Michael,Talkowski, Xuefang,Zhao, Ramita,Dewan, Ali,Stark, Anindita,Ray, Sultana,Solaiman, Pilar,Alvarez Jerez, Laksh,Malik, Ted M,Dawson, Liana S,Rosenthal, Marilyn S,Albert, Olga,Pletnikova, Juan C,Troncoso, Mario,Masellis, Julia,Keith, Sandra E,Black, Luigi,Ferrucci, Susan M,Resnick, Toshiko,Tanaka, Eric,Topol, Ali,Torkamani, Pentti,Tienari, Tatiana M,Foroud, Bernardino,Ghetti, John E,Landers, Mina,Ryten, Huw R,Morris, John A,Hardy, Letizia,Mazzini, Sandra,D'Alfonso, Cristina,Moglia, Andrea,Calvo, Geidy E,Serrano, Thomas G,Beach, Tanis,Ferman, Neill R,Graff-Radford, Bradley F,Boeve, Zbigniew K,Wszolek, Dennis W,Dickson, Adriano,Chiò, David A,Bennett, Philip L,De Jager, Owen A,Ross, Clifton L,Dalgard, J Raphael,Gibbs, Bryan J,Traynor, Sonja W,Scholz

Cell genomics · 2023-05-04

pmid:37388914

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

pmid:22406228

STRipy - STRs database (C9ORF72 locus)

stripy:C9ORF72

Relationship between C9orf72 repeat size and clinical phenotype.

Sara,Van Mossevelde, Julie,van der Zee, Marc,Cruts, Christine,Van Broeckhoven

Current opinion in genetics & development · 2017-03-17

pmid:28319737

Analysis of normal

Silvia,Peverelli, Alberto,Brusati, Valeria,Casiraghi, Marta Nice,Sorce, Sabrina,Invernizzi, Serena,Santangelo, Claudia,Morelli, Federico,Verde, Vincenzo,Silani, Nicola,Ticozzi, Antonia,Ratti

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

pmid:38099605

C9orf72 and triplet repeat disorder RNAs: G-quadruplex formation, binding to PRC2 and implications for disease mechanisms.

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

pmid:31048495

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

Evan,Udine, NiCole A,Finch, Mariely,DeJesus-Hernandez, Jazmyne L,Jackson, Matthew C,Baker, Siva Arumugam,Saravanaperumal, Eric,Wieben, Mark T W,Ebbert, Jaimin,Shah, Leonard,Petrucelli, Rosa,Rademakers, Björn,Oskarsson, Marka,van Blitterswijk

Molecular neurodegeneration · 2024-12-21

pmid:39709476

Age-related penetrance of the C9orf72 repeat expansion.

Natalie A,Murphy, Karissa C,Arthur, Pentti J,Tienari, Henry,Houlden, Adriano,Chiò, Bryan J,Traynor

Scientific reports · 2017-05-18

pmid:28522837

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

omim:105500

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

Rita,Sattler, Bryan J,Traynor, Janice,Robertson, Ludo,Van Den Bosch, Sami J,Barmada, Clive N,Svendsen, Matthew D,Disney, Tania F,Gendron, Philip C,Wong, Martin R,Turner, Adam,Boxer, Suma,Babu, Michael,Benatar, Michael,Kurnellas, Jonathan D,Rohrer, Christopher J,Donnelly, Lynette M,Bustos, Kendall,Van Keuren-Jensen, Penny A,Dacks, Marwan N,Sabbagh

Neurology and therapy · 2023-10-17

pmid:37847372

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

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)

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

pmid:41957010

Population-scale repeat expansions elucidate disease risk and brain atrophy.

Vijay Kumar,Pounraja, Jae Hoon,Sul, Joseph,Herman, Sean,O'Keeffe, Veera,Rajagopal, Xiaodong,Bai, Michael D,Kessler, Neelroop,Parikshak, Karl,Landheer, Xingmin,Zhang, Sean,Yu, Lance,Zhang, Michelle G,LeBlanc, Jennifer,Rico-Varela, Frederic,Grau, Sarah,Wolf, Sriramkumar,Sundaramoorthy, Farshid,Sepehrband, Eli A,Stahl, Yuda,Huo, Mohsin,Ahmed, Susan,Croll, William,Salerno, John D,Overton, Jonathan,Marchini, Jeffrey,Reid, Luca A,Lotta, Aris,Baras, Goncalo R,Abecasis, Giovanni,Coppola, Sahar,Gelfman

Nature · 2026-04-08

pmid:41951733

Somatic mosaicism in ALS and FTD identifies focal mutations associated with widespread degeneration.

Zinan,Zhou, Junho,Kim, August Yue,Huang, Matthew,Nolan, Junseok,Park, Ryan,Doan, Taehwan,Shin, Michael B,Miller, Mingyun,Bae, Boxun,Zhao, Jinhyeong,Kim, Brian,Chhouk, Katherine,Morillo, Rebecca C,Yeh, Connor,Kenny, Jennifer E,Neil, Chao-Zong,Lee, Takuya,Ohkubo, John,Ravits, Olaf,Ansorge, Lyle W,Ostrow, Clotilde,Lagier-Tourenne, Eunjung Alice,Lee, Christopher A,Walsh

Nature genetics · 2026-04-15

pmid:41986690

C9orf72 gene repeat expansion phenotype profile of motor neurone disease in Portugal.

Cláudia,Santos Silva, Marta,Gormicho, Sara,Simão, Ana Catarina,Pronto-Laborinho, Inês,Alves, Susana,Pinto, Miguel,Oliveira Santos, Mamede,de Carvalho

Journal of the neurological sciences · 2024-08-30

pmid:39226712

Simultaneous and independent detection of C9ORF72 alleles with low and high number of GGGGCC repeats using an optimised protocol of Southern blot hybridisation.

Vladimir L,Buchman, Johnathan,Cooper-Knock, Natalie,Connor-Robson, Adrian,Higginbottom, Janine,Kirby, Olga D,Razinskaya, Natalia,Ninkina, Pamela J,Shaw

Molecular neurodegeneration · 2013-04-08

pmid:23566336

Long-read sequencing across the C9orf72 'GGGGCC' repeat expansion: implications for clinical use and genetic discovery efforts in human disease.

Mark T W,Ebbert, Stefan L,Farrugia, Jonathon P,Sens, Karen,Jansen-West, Tania F,Gendron, Mercedes,Prudencio, Ian J,McLaughlin, Brett,Bowman, Matthew,Seetin, Mariely,DeJesus-Hernandez, Jazmyne,Jackson, Patricia H,Brown, Dennis W,Dickson, Marka,van Blitterswijk, Rosa,Rademakers, Leonard,Petrucelli, John D,Fryer

Molecular neurodegeneration · 2018-08-21

pmid:30126445

Direct targeting of C9ORF72 repeat RNA with fluorinated antisense oligonucleotides.

Halle M,Barber, Mansi A,Parasrampuria, Jerónimo,Jurado-Arjona, Andrea,Gamir-Morralla, Benedikt,Berninger, Carlos,González, Keith T,Gagnon, Masad J,Damha, Miguel,Garavís

Nucleic acids research · 2026-04-23

pmid:42033225

Neuropathological analysis of an ALS patient carrying a SOD1 missense variant and a C9orf72 repeat expansion.

Tomoko,Miki, Sibylle,De Bertier, Maria-Del-Mar,Amador, Mélusine,Nicolas, Claire,Guissart, Marion,Deret, Elisa,Teyssou, François,Muratet, Delphine,Bohl, Christian S,Lobsiger, Séverine,Boillée, Florence,Esselin, François,Salachas, Stéphanie,Millecamps, Danielle,Seilhean

Acta neuropathologica · 2026-04-17

pmid:41995858

Microprotein Regulates G-quadruplex Driven RNA Aggregation.

Bikash R,Sahoo, Janakraj,Bhattrai, Arnav,Sharma, Ursula,Jakob, James Ca,Bardwell

bioRxiv : the preprint server for biology · 2026-04-15

pmid:41993388