|Title||C9orf72 hexanucleotide repeat expansions in clinical Alzheimer disease.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Harms, M, Benitez, BA, Cairns, N, Cooper, B, Cooper, P, Mayo, K, Carrell, D, Faber, K, Williamson, J, Bird, T, Diaz-Arrastia, R, Foroud, TM, Boeve, BF, Graff-Radford, NR, Mayeux, R, Chakraverty, S, Goate, AM, Cruchaga, C|
|Corporate Authors||NIA-LOAD/NCRAD Family Study Consortium|
|Date Published||2013 Jun|
|Keywords||Adult, Aged, Aged, 80 and over, Alzheimer Disease, Case-Control Studies, Cohort Studies, DNA Repeat Expansion, Female, Humans, Male, Middle Aged, Pedigree, Proteins|
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.
|Alternate Journal||JAMA Neurol|
|PubMed Central ID||PMC3681841|
|Grant List||K08 NS075094 / NS / NINDS NIH HHS / United States |
P30 NS069329 / NS / NINDS NIH HHS / United States
P50 AG005134 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
P50 AG16574 / AG / NIA NIH HHS / United States
R01 AG035083 / AG / NIA NIH HHS / United States
R01 AG041797 / AG / NIA NIH HHS / United States
R01 AG32306 / AG / NIA NIH HHS / United States
R01 MH060009 / MH / NIMH NIH HHS / United States
U01 AG06786 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States