title: C9orf72 hexanucleotide repeat expansions in clinical Alzheimer disease.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Harms
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Benitez
authors.forename: Nigel
authors.initials: N
authors.lastname: Cairns
authors.forename: Breanna
authors.initials: B
authors.lastname: Cooper
authors.forename: Paul
authors.initials: P
authors.lastname: Cooper
authors.forename: Kevin
authors.initials: K
authors.lastname: Mayo
authors.forename: David
authors.initials: D
authors.lastname: Carrell
authors.forename: Kelley
authors.initials: K
authors.lastname: Faber
authors.forename: Jennifer
authors.initials: J
authors.lastname: Williamson
authors.forename: Tom
authors.initials: T
authors.lastname: Bird
authors.forename: Ramon
authors.initials: R
authors.lastname: Diaz-Arrastia
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Foroud
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.forename: Sumitra
authors.initials: S
authors.lastname: Chakraverty
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000235:genetics*; D000073885:C9orf72 Protein; D016022:Case-Control Studies; D015331:Cohort Studies; D042622:DNA Repeat Expansion / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D011506:Proteins / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins