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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 (FTLDTDP)
(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 to29%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.