C9ORF72 hexanucleotide repeat number in frontotemporal lobar degeneration: A genotype-phenotype correlation study

Luisa Benussi, Giacomina Rossi, Michela Glionna, Elisa Tonoli, Elena Piccoli, Silvia Fostinelli, Anna Paterlini, Rosa Flocco, Diego Albani, Roberta Pantieri, Cristina Cereda, Gianluigi Forloni, Fabrizio Tagliavini, Giuliano Binetti, Roberta Ghidoni

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)799-808
Number of pages10
JournalJournal of Alzheimer's Disease
Issue number4
Publication statusPublished - 2014


  • C9ORF72 repeat units number
  • Endophenotype
  • Frontotemporal dementia
  • Genetic testing
  • Mutation penetrance
  • Mutation prevalence
  • Pedigree

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology


Dive into the research topics of 'C9ORF72 hexanucleotide repeat number in frontotemporal lobar degeneration: A genotype-phenotype correlation study'. Together they form a unique fingerprint.

Cite this