Original Contribution |

C9orf72 Hexanucleotide Repeat Expansions in Clinical Alzheimer Disease

Matthew Harms, MD; Bruno A. Benitez, MD; Nigel Cairns, PhD; Breanna Cooper, BS; Paul Cooper, BS; Kevin Mayo, BA; David Carrell, BS; Kelley Faber, MS; Jennifer Williamson, MS; Tom Bird, MD; Ramon Diaz-Arrastia, MD; Tatiana M. Foroud, PhD; Bradley F. Boeve, MD; Neill R. Graff-Radford, MBChB; Richard Mayeux, MD, MS; Sumitra Chakraverty, MS; Alison M. Goate, PhD; Carlos Cruchaga, PhD; for the NIA-LOAD/NCRAD Family Study Consortium
JAMA Neurol. 2013;70(6):736-741. doi:10.1001/2013.jamaneurol.537.
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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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Graphic Jump Location

Figure 1. Alzheimer disease (AD) pedigrees carrying abnormal C9orf72 repeat expansions. Fully shaded symbols indicate autopsy-confirmed AD. Clinical diagnoses were made using National Institute of Neurological and Communication Disorders and Stroke–Alzheimer Disease and Related Disorders Association criteria, with three-quarters and one-half shading indicating probable and possible AD, respectively. + indicates the presence of repeat expansion genotypes and − indicates their absence. The absence of a genotype symbol indicates that DNA was not available for analysis. An arrow marks the proband of each pedigree. ALV indicates age at last visit; AO, age at onset.

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Graphic Jump Location

Figure 2.C9orf72 repeat expansions correlate with an earlier age at onset. Age at onset was analyzed for association with repeat expansion genotypes by the Kaplan-Meier method and tested for significant differences using a proportional hazards model (proc PHREG; SAS Institute Inc). Repeat expansion carriers show an earlier age at onset than noncarriers (mean [SD], 68.25 [5.8] vs 71.4 [6.8] years; P = .04).




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