Expansion of a hexanucleotide repeat in the C9ORF72 gene has been identified as 
the most common pathogenic mutation in families with autosomal dominant 
frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis. 
Herein we investigated frequency and penetrance of the C9ORF72 hexanucleotide 
repeat pathological expansion in a large cohort of familial and sporadic FTLD 
and related disorders (FTLD and related disorders, n = 388; Controls, n = 201). 
Moreover, we weighed the impact of C9ORF72 genotype on clinical phenotype taking 
into account the hexanucleotide repeat units number as a possible disease 
modifier. In our cohort, the C9ORF72 pathological expansion: (i) showed a 
prevalence of 7.5%; (ii) showed a full penetrance by the age of 80; (iii) was 
rarely found in sporadic patients; (iv) was solely associated with FTLD; (v) was 
mainly associated with bvFTD clinical subtype; and (vi) was associated with 
earlier age of onset in the youngest generation compared with the previous 
generation within a pedigree. Interestingly, intermediate C9ORF72 expansion had 
a risk effect in familial/sporadic FTLD. Eventually, the C9ORF72 repeat units 
number influenced the disease phenotype in terms of age of onset and associated 
clinical subtype. Genome-wide studies in well characterized clinical cohorts 
will be essential in order to decipher pathways of disease expression in 
C9ORF72-associated neurodegeneration.