Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study
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BACKGROUND: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). METHODS: We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. FINDINGS: In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. INTERPRETATION: A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).
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Conditional Nlk knockout in adult animals is well-tolerated.
“Conditional Nlk knockout in adult animals is well-tolerated, however (59), and Nlk haploinsufficiency (Nlk+/−) is protective in several neurodegenerative disease models, including TDP43-overexpressing mice (15–18).”
From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [59]
The Results and Discussion passages concern C9orf72 repeat expansions in people with ALS or FTD, not conditional Nlk knockout in adult animals. Searches for the claimed knockout and for Nlk/Nemo-like kinase found no passage addressing its tolerability; the cited paper’s page numbers were not available in our copy. (LLM, conf=0.78)
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“First, we examined the survival of iPSC-derived neurons carrying C9ORF72 expansions, the most prevalent mutation underlying familial ALS and FTLD-TDP in Europe and North America (59).”
- Authors
- Majounie, E., Renton, A. E., Mok, K., Dopper, E. G., Waite, A., Rollinson, S., Chiò, A., Restagno, G., Nicolaou, N., Simon-Sanchez, J., van Swieten, J. C., Abramzon, Y., Johnson, J. O., Sendtner, M., Pamphlett, R., Orrell, R. W., Mead, S., Sidle, K. C., Houlden, H., Rohrer, J. D., Morrison, K. E., Pall, H., Talbot, K., Ansorge, O., Hernandez, D. G., Arepalli, S., Sabatelli, M., Mora, G., Corbo, M., Giannini, F., Calvo, A., Englund, E., Borghero, G., Floris, G. L., Remes, A. M., Laaksovirta, H., McCluskey, L., Trojanowski, J. Q., Van Deerlin, V. M., Schellenberg, G. D., Nalls, M. A., Drory, V. E., Lu, C.-S., Yeh, T.-H., Ishiura, H., Takahashi, Y., Tsuji, S., Le Ber, I., Brice, A., Drepper, C., Williams, N., Kirby, J., Shaw, P., Hardy, J., Tienari, P. J., Heutink, P., Morris, H. R., Pickering-Brown, S., & Traynor, B. J.
- Affiliations
- National Institutes of Health (US)
- UCL Queen Square Institute of Neurology (GB)
- Erasmus MC (NL)
- Cardiff University (GB)
- University of Manchester (GB)
- University of Turin (IT)
- Ospedale Sant'Anna (IT)
- University of Würzburg (DE)
- The University of Sydney (AU)
- MRC Prion Unit (GB)
- University of Birmingham (GB)
- University Hospitals Birmingham NHS Foundation Trust (GB)
- John Radcliffe Hospital (GB)
- Università Cattolica del Sacro Cuore (IT)
- Fondazione Salvatore Maugeri (IT)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- University of Siena (IT)
- Lund University (SE)
- University of Cagliari (IT)
- Oulu University Hospital (FI)
- University of Helsinki (FI)
- University of Pennsylvania (US)
- Tel Aviv Sourasky Medical Center (IL)
- Chang Gung University (TW)
- University of Tokyo Hospital (JP)
- Centre National de la Recherche Scientifique (FR)
- University of Sheffield (GB)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Royal Gwent Hospital (GB)
- Corresponding author
- Traynor, Bryan J
- ORCID
- Renton, Alan E
- Mok, Kin
- Dopper, Elise GP
- Waite, Adrian
- Rollinson, Sara
- Chiò, Adriano
- Sendtner, Michael
- Pamphlett, Roger
- Mead, Simon
- Houlden, Henry
- Rohrer, Jonathan D
- Morrison, Karen E
- Talbot, Kevin
- Ansorge, Olaf
- Hernandez, Dena G
- Sabatelli, Mario
- Mora, Gabriele
- Corbo, Massimo
- Calvo, Andrea
- Englund, Elisabet
- Borghero, Giuseppe
- Laaksovirta, Hannu
- Trojanowski, John Q
- Schellenberg, Gerard D
- Lu, Chin-Song
- Yeh, Tu-Hsueh
- Ishiura, Hiroyuki
- Takahashi, Yuji
- Tsuji, Shoji
- Brice, Alexis
- Drepper, Carsten
- Williams, Nigel
- Kirby, Janine
- Shaw, Pamela
- Hardy, John
- Tienari, Pentti J
- Heutink, Peter
- Morris, Huw R
- Pickering-Brown, Stuart
- Traynor, Bryan J
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2012-04
- Volume
- 11
- Issue
- 4
- Pages
- 323-330
- ISSN
- 1474-4422 (ISSN-L)
- PMC
- PMC3322422
- OpenAlex
- W2138207816
- Cited by
- 1,210
- References
- 3
- Citations by year
- 2026: 49 · 2025: 57 · 2024: 87 · 2023: 62 · 2022: 64 · 2021: 77 · 2020: 111 · 2019: 72 · 2018: 90 · 2017: 93 · 2016: 92 · 2015: 110 · 2014: 90 · 2013: 105 · 2012: 49
- FWCI
- 74.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Lancet Neurology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- ePrints Soton (University of Southampton) (acceptedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- HAL (submittedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
- Archive of Doctoral Theses and Digital Collections (University of Calabria) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- AIRUS (submittedVersion)
- UnissResearch (Università degli Studi di Sassari) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion, other-oa)
- Online Publication Service of Würzburg University (Würzburg University) (submittedVersion, cc-by)
- Pure Amsterdam UMC (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Use Siena air (University of Siena) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Packard Center for ALS Research at Hopkins (BJT), the ALS Association (BJT, ACh), Microsoft Research (BJT, PJT), AriSLA (BJT, ACh, MSa), Hersenstichting Nederland Fellowship project B08.03 and the Neuroscience Campus Amsterdam (JS-S), Nuts Ohra Fonds (JvS), Stichting Dioraphte (09020300)
- UK Motor Neurone Disease Association ((HM [Motor Neurone Disease Association grant 6057], JH, RWO, KEM, PJS MNDA Grant 6700/3))
- The Medical Research Council UK (JH, HH, SP-B), the Wellcome Trust ((JH, HH, PJS; 069388/z/02/z))
- the French Agency for Research (ANR-08-MNPS-009-01; AB and ILB), France Alzheimer–Union Nationale des Associations Alzheimer (ILB) and Institut de France Subvention de la Fondation Thierry et Annick DESMAREST (ILB), and the European Community's Health Seventh Framework Programme (259867)
- Deutsche Forschungsgemeinschaft (grant SFT.581, TP4)
- National Health and Medical Research Council (402703)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- hexanucleotide repeat expansion, amyotrophic lateral sclerosis, frontotemporal dementia, mutation frequency, founder haplotype, ethnic differences, repeat-primed PCR, haplotype analysis, neurodegenerative disease genetics
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Child, Child, Preschool, Chromosomes, Human, Pair 9, Cross-Sectional Studies, Female, Genotype, Humans, Male, Middle Aged, Cohort Studies, Open Reading Frames, Age of Onset, DNA Repeat Expansion, Young Adult, Genetic Loci, Frontotemporal Dementia
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