title: C9ORF72 repeat expansion in clinical and neuropathologic frontotemporal dementia cohorts.
abstract: OBJECTIVE
  To determine the frequency of a hexanucleotide repeat expansion in C9ORF72, a gene of unknown function implicated in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), in Australian FTD patient cohorts and to examine the clinical and neuropathologic phenotypes associated with this expansion.
  
  
  METHODS
  We examined a clinically ascertained FTD cohort (n = 89) and a neuropathologically ascertained cohort of frontotemporal lobar degeneration cases with TDP-43 pathology (FTLD-TDP) (n = 22) for the C9ORF72 hexanucleotide repeat expansion using a repeat primed PCR assay. All expansion-positive patients were genotyped for rs3849942, a surrogate marker for the chromosome 9p21 risk haplotype previously associated with FTD and ALS.
  
  
  RESULTS
  The C9ORF72 repeat expansion was detected in 10% of patients in the clinically diagnosed cohort, rising to 29% in those with a positive family history of early-onset dementia or ALS. The prevalence of psychotic features was significantly higher in expansion-positive cases (56% vs 14%). In the pathology cohort, 41% of TDP-43-positive cases harbored the repeat expansion, and all exhibited type B pathology. One of the 17 expansion-positive probands was homozygous for the "nonrisk" G allele of rs3849942.
  
  
  CONCLUSIONS
  The C9ORF72 repeat expansion is a relatively common cause of FTD in Australian populations, and is especially common in those with FTD-ALS, psychotic features, and a strong family history. Detection of a repeat expansion on the 9p21 putative "nonrisk" haplotype suggests that not all mutation carriers are necessarily descended from a common founder and indicates that the expansion may have occurred on multiple haplotype backgrounds.
authors.affiliation: Neuroscience Research Australia, Sydney, Australia.
authors.forename: Carol
authors.initials: C
authors.lastname: Dobson-Stone
authors.forename: Marianne
authors.initials: M
authors.lastname: Hallupp
authors.forename: Lauren
authors.initials: L
authors.lastname: Bartley
authors.forename: Claire E
authors.initials: CE
authors.lastname: Shepherd
authors.forename: Glenda M
authors.initials: GM
authors.lastname: Halliday
authors.forename: Peter R
authors.initials: PR
authors.lastname: Schofield
authors.forename: John R
authors.initials: JR
authors.lastname: Hodges
authors.forename: John B J
authors.initials: JB
authors.lastname: Kwok
mesh_terms: D017668:Age of Onset; D000368:Aged; D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001315:Australia; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D011618:Psychotic Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins