C9orf72 hexanucleotide repeat expansions in clinical alzheimer disease

Matthew Harms, Bruno A. Benitez, Nigel Cairns, Breanna Cooper, Paul Cooper, Kevin Mayo, David Carrell, Kelley Faber, Jennifer Williamson, Tom Bird, Ramon Diaz-Arrastia, Tatiana Foroud, Bradley F. Boeve, Neill R. Graff-Radford, Richard Mayeux, Sumitra Chakraverty, Alison M. Goate, Carlos Cruchaga

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

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.Twoadditional 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.

Original languageEnglish
Pages (from-to)736-741
Number of pages6
JournalJAMA Neurology
Volume70
Issue number6
DOIs
StatePublished - 2013

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Chromosomes, Human, Pair 9
Open Reading Frames
Alzheimer Disease
National Institute on Aging (U.S.)
Frontotemporal Dementia
Mutation
Genes
Case-Control Studies
Cohort Studies
Alleles
Genotype
Outcome Assessment (Health Care)
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Harms, M., Benitez, B. A., Cairns, N., Cooper, B., Cooper, P., Mayo, K., ... Cruchaga, C. (2013). C9orf72 hexanucleotide repeat expansions in clinical alzheimer disease. JAMA Neurology, 70(6), 736-741. https://doi.org/10.1001/2013.jamaneurol.537

C9orf72 hexanucleotide repeat expansions in clinical alzheimer disease. / Harms, Matthew; Benitez, Bruno A.; Cairns, Nigel; Cooper, Breanna; Cooper, Paul; Mayo, Kevin; Carrell, David; Faber, Kelley; Williamson, Jennifer; Bird, Tom; Diaz-Arrastia, Ramon; Foroud, Tatiana; Boeve, Bradley F.; Graff-Radford, Neill R.; Mayeux, Richard; Chakraverty, Sumitra; Goate, Alison M.; Cruchaga, Carlos.

In: JAMA Neurology, Vol. 70, No. 6, 2013, p. 736-741.

Research output: Contribution to journalArticle

Harms, M, Benitez, BA, Cairns, N, Cooper, B, Cooper, P, Mayo, K, Carrell, D, Faber, K, Williamson, J, Bird, T, Diaz-Arrastia, R, Foroud, T, Boeve, BF, Graff-Radford, NR, Mayeux, R, Chakraverty, S, Goate, AM & Cruchaga, C 2013, 'C9orf72 hexanucleotide repeat expansions in clinical alzheimer disease', JAMA Neurology, vol. 70, no. 6, pp. 736-741. https://doi.org/10.1001/2013.jamaneurol.537
Harms M, Benitez BA, Cairns N, Cooper B, Cooper P, Mayo K et al. C9orf72 hexanucleotide repeat expansions in clinical alzheimer disease. JAMA Neurology. 2013;70(6):736-741. https://doi.org/10.1001/2013.jamaneurol.537
Harms, Matthew ; Benitez, Bruno A. ; Cairns, Nigel ; Cooper, Breanna ; Cooper, Paul ; Mayo, Kevin ; Carrell, David ; Faber, Kelley ; Williamson, Jennifer ; Bird, Tom ; Diaz-Arrastia, Ramon ; Foroud, Tatiana ; Boeve, Bradley F. ; Graff-Radford, Neill R. ; Mayeux, Richard ; Chakraverty, Sumitra ; Goate, Alison M. ; Cruchaga, Carlos. / C9orf72 hexanucleotide repeat expansions in clinical alzheimer disease. In: JAMA Neurology. 2013 ; Vol. 70, No. 6. pp. 736-741.
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N2 - 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.Twoadditional 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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