FTDALS1 C9orf72

Disease ID
FTDALS1
Gene ID
C9orf72
Updated
Feb 5, 2025
v2.2.1

Disease

Name
Frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS)
Inheritance
Autosomal dominant
Description
Pure frontotemporal dementia, pure amyotrophic lateral sclerosis or combination of the two1 .
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 3002 . Related individuals to patients with C9orf72-ALS appear at an increased risk of disease regardless of carrier status3,4 . 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(Typical)Years20  9150  64
Age of Onset Details
Typical: 50-64; Range: 20-915 .

Locus

Details
FTD and ALS form a clinical spectrum6,7 . The clinical ranges of the C9orf72 locus remain ambiguous8 : most healthy controls have alleles up to 24 repeats9 yet 24-30 repeats are associated with ALS2 and while 60 repeats is frequently used as a threshold for uncertain alleles, the exact threshold of pathogenicity remains unclear5,10 . 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 repeats10,12 . 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 .
Year
201116
Location in Gene
Intron 1 or 5' UTR depending on transcript
Gene Strand

Alleles

Ref. Motif
GGCCCC
Pathogenic (ref.)
GGCCCC
Pathogenic (gene)
CCGGGG
BenignIntermediatePathogenicUnits2  2324  60251  4,088

gnomAD

References

Direct supporting references for info on this page.

1
Repeat expansion disorders.
Zhongbo,Chen, Huw R,Morris, James,Polke, Nicholas W,Wood, Sonia,Gandhi, Mina,Ryten, Henry,Houlden, Arianna,Tucci
Practical neurology · 2024-09-30
pmid:39349043
2
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
3
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
4
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
5
C9orf72 Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis
Helena,Gossye, Sebastiaan,Engelborghs, Christine,Van Broeckhoven, Julie,Zee
GeneReviews® · 1993-01-01
genereviews:NBK268647
6
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
7
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
8
STRipy - STRs database (C9ORF72 locus)
stripy:C9ORF72
9
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
10
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
11
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
12
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
13
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
15
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
16
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)