FTDALS1 C9orf72

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 300². Related individuals to patients with C9orf72-ALS appear at an increased risk of disease regardless of carrier status^3,4. C9orf72-FTD is estimated to be 0.04-134:100,000⁵, 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 ancestry⁵.

Age of Onset Details

Typical: 50-64; Range: 20-91⁵.

Locus

hg19

chr9:27573482-27573544

hg38

chr9:27573484-27573546

t2t

chr9:27584063-27584155

Details

FTD and ALS form a clinical spectrum^6,7. The clinical ranges of the C9orf72 locus remain ambiguous⁸: most healthy controls have alleles up to 24 repeats⁹yet 24-30 repeats are associated with ALS²and while 60 repeats is frequently used as a threshold for uncertain alleles, the exact threshold of pathogenicity remains unclear^5,10. Repeat of 80 motifs and lower appear to have delayed onset for any phenotype⁹. >250 repeats are associated with a full FTD/ALS disease state¹¹, but pathogenic alleles can range from 30 to more than 4000 repeats^10,12. Penetrance appears to also be age-dependent, with environmental factors and specific phenotypes associated with sex and age at onset¹³. Methylation appears to increase with expansion length and age¹².

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 region¹⁴. Addiitonal mechanisms theorized include protein loss of function and RNA gain of function¹⁵. Multiple cell types in the prefrontal cortex, including oligodendrocytes, microglia, astrocytes, and neurons, appear impacted during pathogenesis¹⁶.

Year

2011¹⁷

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

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

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)

Canonical translation factors eIF1A and eIF5B modulate the initiation step of repeat-associated non-AUG translation.

Hayato,Ito, Kodai,Machida, Yuzo,Fujino, Mayuka,Hasumi, Soyoka,Sakamoto, Yoshitaka,Nagai, Hiroaki,Imataka, Hideki,Taguchi

Nucleic acids research · 2025-09-23

pmid:41063344

Patient-derived Induced Pluripotent Stem Cells with a C9orf72 Expansion as a Model to Study Frontotemporal Dementia Pathologies.

Sonia,Infante-Tadeo, Diane L,Barber

Molecular biology of the cell · 2025-10-08

pmid:41060790

Dynamic changes in chromosome and nuclear architecture during maturation of normal and ALS C9orf72 motor neurons.

Özgün,Uyan, Snehal,Sambare, Marlies E,Oomen, Nicholas,Wightman, Allana,Schooley, Joseph R,Klim, Houda,Belaghzal, Özkan,Aydemir, Betul,Akgol-Oksuz, Zeynep Sena Agim,Uslu, Kevin,Eggan, Robert H,Brown, Job,Dekker

bioRxiv : the preprint server for biology · 2025-09-22

pmid:41040221

Generation of

Rachel,Coneys, Alexander J,Cammack, Remya R,Nair, David,Thompson, Jonas,Mechtersheimer, Mireia,Carcolé, Yashica,Gupta, Gabriel E,Rech, Michael,Flower, Niamh,O'Brien, Marc-David,Ruepp, Sarah,Mizielinska, Fiona,Ducotterd, Sarah J,Tabrizi, Elizabeth M C,Fisher, Thomas J,Cunningham, Michael,Ward, William C,Skarnes, Adrian M,Isaacs

bioRxiv : the preprint server for biology · 2025-02-11

pmid:41030957

Dissecting epigenetic age acceleration in amyotrophic lateral sclerosis.

Polina,Merbaum, Ramona,Zwamborn, Paul,Hop, Project MinE Als,Sequencing Consortium, Wouter,van Rheenen, Jan,Veldink

Epigenomics · 2025-09-30

pmid:41025901

Accurate DNA Methylation Predictor for C9orf72 Repeat Expansion Alleles in the Pathogenic Range.

Naren,Ramesh, Alexandria,Evans, Kevin,Wojta, Zhongan,Yang, Marco P,Boks, René S,Kahn, Sterre C M,de Boer, Sven J,van der Lee, Yolande A L,Pijnenburg, Lianne M,Reus, Roel A,Ophoff

HGG advances · 2025-09-29

pmid:41024438

Repeat Variants, Biomarkers, and Molecular Signatures in Parkinson's Disease:

Jose Miguel,Laffita-Mesa, Martin,Paucar, Per,Svenningsson

International journal of molecular sciences · 2025-09-20

pmid:41009775

Frontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage.

Nadine,Huber, Tomi,Hietanen, Sami,Heikkinen, Anastasia,Shakirzyanova, Dorit,Hoffmann, Hannah,Rostalski, Ashutosh,Dhingra, Salvador,Rodriguez-Nieto, Sari,Kärkkäinen, Marja,Koskuvi, Eila,Korhonen, Päivi,Hartikainen, Katri,Pylkäs, Johanna,Krüger, Tarja,Malm, Mari,Takalo, Mikko,Hiltunen, Jari,Koistinaho, Anne M,Portaankorva, Eino,Solje, Annakaisa,Haapasalo

Molecular psychiatry · 2025-09-26

pmid:41006764

IRE1/Xbp1 promotes the clearance of poly(GR) dipeptide repeats in Amyotrophic Lateral Sclerosis.

Yu,Li, Dongyue,Liu, Shuangxi,Li

The Journal of biological chemistry · 2025-09-24

pmid:41005474