A Pan‐ E uropean Study of the C9orf72 Repeat Associated with FTLD : Geographic Prevalence, Genomic Instability, and Intermediate Repeats

We assessed the geographical distribution of C9orf72 G 4 C 2 expansions in a pan‐ E uropean frontotemporal lobar degeneration ( FTLD ) cohort ( n  = 1,205), ascertained by the E uropean E arly‐ O nset D ementia ( EOD ) consortium. Next, we performed a meta‐analysis of our data and that of other E uropean studies, together 2,668 patients from 15 W estern E uropean countries. The frequency of the C9orf72 expansions in W estern E urope was 9.98% in overall FTLD , with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were F inland and S weden with overall frequencies of respectively 29.33% and 20.73%, but also S pain with 25.49%. In contrast, prevalence in G ermany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7–24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss‐of‐function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC ‐rich low complexity sequence adjacent to the G 4 C 2 repeat in C9orf72 expansion carriers ( P  < 0.001) with the most common indel creating one long contiguous imperfect G 4 C 2 repeat, which is likely more prone to replication slippage and pathological expansion.