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.

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 300³. Related individuals to patients with C9orf72-ALS appear at an increased risk of disease regardless of carrier status^4,5. C9orf72-FTD is estimated to be 0.04-134:100,000⁶, 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 ancestry⁶.

Age of Onset Details

Typical: 50-64; Range: 20-91⁶.

Locus

hg19

chr9:27573482-27573544

hg38

chr9:27573484-27573546

t2t

chr9:27584063-27584155

Details

FTD and ALS form a clinical spectrum^7,8. The clinical ranges of the C9orf72 locus remain ambiguous⁹: most healthy controls have alleles up to 24 repeats¹⁰yet 24-30 repeats are associated with ALS³and while 60 repeats is frequently used as a threshold for uncertain alleles, the exact threshold of pathogenicity remains unclear^6,11. Repeats of 80 motifs and lower appear to have delayed onset for any phenotype¹⁰. >250 repeats are associated with a full FTD/ALS disease state¹², but pathogenic alleles can range from 30 to more than 4000 repeats^11,13. Penetrance appears to also be age-dependent, with environmental factors and specific phenotypes associated with sex and age at onset¹⁴. Methylation appears to increase with expansion length and age¹³.

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 region¹⁵. Addiitonal mechanisms theorized include protein loss of function and RNA gain of function¹⁶. Multiple cell types in the prefrontal cortex, including oligodendrocytes, microglia, astrocytes, and neurons, appear impacted during pathogenesis¹⁷.

Year

2011¹⁸

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

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

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

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)

Ginsenoside compound K inhibited the gelation of GGGGCC repeats and regulated co-aggregation with arginine-rich poly-dipeptides in C9orf72-related ALS.

Youduan,Li, Shujie,Liu, Lingling,Cao, Ming,Zhu, Shuang,Lin, Xinxin,Wang, Zhidong,Qiu, Ye,Teng

International journal of biological macromolecules · 2026-02-26

pmid:41763422

Short tandem repeat expansions in patients with neurodegenerative dementia.

Yuan,Zhu, Xuewen,Xiao, Yiliang,Liu, Zheng,Wang, Tengfei,Luo, Tianyan,Xu, Qijie,Yang, Xiaoli,Hao, Cong,Zhang, Sizhe,Zhang, Shilin,Luo, Yafang,Zhou, Xinxin,Liao, Yun,Tian, Ling,Weng, Liangjuan,Fang, Beisha,Tang, Bin,Jiao, Jinchen,Li, Lu,Shen

EBioMedicine · 2026-02-26

pmid:41762523

KIF5A and ALS: a clinical and genetic description of a case series and review of literature.

Anna,D'Amico, Roberta,Cucunato, Giuseppe,Schirò, Giuseppe,Salemi, Paolo,Ragonese, Vincenzo,La Bella, Paolo,Aridon, Marco,D'Amelio

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026-02-28

pmid:41760955

C9orf72-ALS mutation drives basal mitophagy impairments in iNeurons.

James A K,Lee, Chloe,Moutin, Sarah,Granger, Katie,Roome, Allan,Shaw, Scott P,Allen, Laura,Ferraiuolo, Pamela J,Shaw, Heather,Mortiboys

Frontiers in cellular neuroscience · 2026-02-11

pmid:41757350

Antisense Dipeptide Repeat Proteins Drive Widescale Purine Metabolism Aberration in

Benjamin,Hall, Lydia,Castelli, Adrian,Higginbottom, Jingxuan,He, Ling-Nan,Zou, Heather,Walker, Miriam,Yagüe-Capilla, Kari E,Wong, David J,Burrows, Jonathan,George, Keaton,Hamer, Jenny M,Tanner, Ergita,Kyrgiou-Balli, Rees,Ross, Herbie,Garland, Erin,Tonkiss, Rachel,George, Christopher P,Webster, Emma F,Smith, Hannah O,Timmons, Jess,Allsop, Nikolas,Stefanidis, Billie D,Ward, Ya-Hui,Lin, J Robin,Highley, Mimoun,Azzouz, Ryan J H,West, Sean G,Rudd, Kurt J De,Vos, Pamela J,Shaw, Guillaume M,Hautbergue, Scott P,Allen

International journal of molecular sciences · 2026-02-18

pmid:41752089

PPAR-Delta Agonist Therapies Did Not Rescue Hallmark Disease Phenotypes in Two Sets of Preclinical Trials in ALS TDP-43 and C9orf72 Model Mice.

David T,Luong, Chenchen,Niu, Eunice,Kim, Nolan,Tanji, Ivy,Duong, Brandon,Galero, Yong-Jie,Zhang, Craig L,Bennett, Albert R,La Spada

International journal of molecular sciences · 2026-02-13

pmid:41751955

Intrathecal (G

Katelyn A,Russell, Amelia A,Shahrabi, Suleyman C,Akerman, Matthew D,Byrne, Jeffrey D,Rothstein, Davide,Trotti, Brigid K,Jensen, Aaron R,Haeusler

bioRxiv : the preprint server for biology · 2026-02-11

pmid:41727102

Increased neuronal activity restores circadian function in Drosophila models of C9orf72-ALS/FTD.

Sho,Inami, Benjamin P,Jenny, Oghenerukevwe,Akpoghiran, Sara I,Gallagher, Alexandra K,Strich, Ayako,Tonoki, Davide,Trotti, Aaron R,Haeusler, Kyunghee,Koh

iScience · 2026-01-24

pmid:41717003

C9orf72-derived dipeptide repeat proteins poly-PR disrupt membrane excitability and synaptic function in cortical neurons.

Shao-Ming,Wang, Jui-Cheng,Chan, Engkarat,Supapatarnun, Chao-Yi,Tsai, Phan Thi Ngoc,Lan, Eddie Feng-Ju,Weng

Neurobiology of disease · 2026-02-13

pmid:41692171