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C9orf72 Hexanucleotide Repeat Expansions in Clinical Alzheimer Disease
Open accessAbstract
IMPORTANCE: Hexanucleotide repeat expansions in the chromosome 9 open reading frame 72 (C9orf72) gene underlie a significant fraction of frontotemporal dementia and amyotrophic lateral sclerosis. OBJECTIVE: To investigate the frequency of C9orf72 repeat expansions in clinically diagnosed late-onset Alzheimer disease (AD). DESIGN, SETTING, AND PATIENTS: This case-control study genotyped the C9orf72 repeat expansion in 872 unrelated familial AD cases and 888 control subjects recruited as part of the National Institute on Aging Late-Onset Alzheimer Disease Family Study cohort, a multisite collaboration studying 1000 families with 2 or more individuals clinically diagnosed as having late-onset AD. MAIN OUTCOMES AND MEASURES: We determined the presence or absence of the C9orf72 repeat expansion by repeat-primed polymerase chain reaction, the length of the longest nonexpanded allele, segregation of the genotype with disease, and clinical features of repeat expansion carriers. RESULTS Three families showed large C9orf72 hexanucleotide repeat expansions. Two additional families carried more than 30 repeats. Segregation with disease could be demonstrated in 3 families. One affected expansion carrier had neuropathology compatible with AD. In the National Institute on Aging Late-Onset Alzheimer Disease Family Study series, the C9orf72 repeat expansions constituted the second most common pathogenic mutation, just behind the PSEN1 A79V mutation, highlighting the heterogeneity of clinical presentations associated with repeat expansions. CONCLUSIONS AND RELEVANCE: C9orf72 repeat expansions explain a small proportion of patients with a clinical presentation indistinguishable from AD, and they highlight the necessity of screening frontotemporal dementia genes in clinical AD cases with strong family history.
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“For instance, C9orf72 expansion mutations are associated not only with ALS/FTLD, but also with symptoms reminiscent of Parkinson disease, Alzheimer disease, Huntington disease, and corticobasal syndrome, reinforcing the imperfect connection between clinical and molecular phenotypes and emphasizing the need for molecular diagnostics [155–164].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [158]
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“Furthermore, it is not known whether higher repeat numbers (but still within the normal range) are associated with the risk for ALS or FTD.”
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Metadata
- Authors
- Harms, M., Benitez, B. A., Cairns, N., Cooper, B., Cooper, P., Mayo, K., Carrell, D., Faber, K., Williamson, J., Bird, T., Diaz-Arrastia, R., Foroud, T. M., Boeve, B. F., Graff-Radford, N. R., Mayeux, R., Chakraverty, S., Goate, A. M., Cruchaga, C., & NIA-LOAD/NCRAD Family Study Consortium, F. T.
- Affiliations
- Washington University in St. Louis (US)
- Indiana University Indianapolis (US)
- Columbia University (US)
- University of Washington (US)
- The University of Texas Southwestern Medical Center (US)
- Mayo Clinic (US)
- Corresponding author
- Cruchaga, Carlos
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2013-06-01
- Volume
- 70
- Issue
- 6
- Pages
- 736
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC3681841
- OpenAlex
- W2035247606
- Cited by
- 102
- References
- 33
- Citations by year
- 2026: 1 · 2024: 4 · 2023: 8 · 2022: 4 · 2021: 7 · 2020: 4 · 2019: 9 · 2018: 6 · 2017: 10 · 2016: 8 · 2015: 9 · 2014: 19 · 2013: 11
- FWCI
- 10.88
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5p30ns069329-02)
- National Institute on Aging (P50‐AG16574, U01AG06786, U01AG006786, R01 AG32306, R01AG035083, R01AG041797, P50AG008702, R01AG032306, P50AG005681, P30AG013846, P50AG005134, U24AG056270, U24AG021886, P30AG062421, P50AG016574)
- National Institute of Mental Health (R01MH060009)
- National Institute of Neurological Disorders and Stroke (P30-NS069329, K08NS075094)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- C9orf72, hexanucleotide repeat expansion, late-onset Alzheimer's disease, familial Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, genetic susceptibility, genetic screening, neuropathology
- MeSH terms
- C9orf72 Protein, Adult, Aged, Aged, 80 and over, Alzheimer Disease, Female, Humans, Male, Middle Aged, Pedigree, Proteins, Cohort Studies, Case-Control Studies, DNA Repeat Expansion
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