C9ORF72 repeat expansion in a large Italian ALS cohort: Evidence of a founder effect

Antonia Ratti, Lucia Corrado, Barbara Castellotti, Roberto Del Bo, Isabella Fogh, Cristina Cereda, Cinzia Tiloca, Carla D'Ascenzo, Alessandra Bagarotti, Viviana Pensato, Michela Ranieri, Stella Gagliardi, Daniela Calini, Letizia Mazzini, Franco Taroni, Stefania Corti, Mauro Ceroni, Gaia D. Oggioni, Kuang Lin, John F. PowellGianni Sorarù, Nicola Ticozzi, Giacomo P. Comi, Sandra D'Alfonso, Cinzia Gellera, Vincenzo Silani

Research output: Contribution to journalArticlepeer-review


A hexanucleotide repeat expansion (RE) in C9ORF72 gene was recently reported as the main cause of amyotrophic lateral sclerosis (ALS) and cases with frontotemporal dementia. We screened C9ORF72 in a large cohort of 259 familial ALS, 1275 sporadic ALS, and 862 control individuals of Italian descent. We found RE in 23.9% familial ALS, 5.1% sporadic ALS, and 0.2% controls. Two cases carried the RE together with mutations in other ALS-associated genes. The phenotype of RE carriers was characterized by bulbar-onset, shorter survival, and association with cognitive and behavioral impairment. Extrapyramidal and cerebellar signs were also observed in few patients. Genotype data revealed that 95% of RE carriers shared a restricted 10-single nucleotide polymorphism haplotype within the previously reported 20-single nucleotide polymorphism risk haplotype, detectable in only 27% of nonexpanded ALS cases and in 28% of controls, suggesting a common founder with cohorts of North European ancestry. Although C9ORF72 RE segregates with disease, the identification of RE both in controls and in patients carrying additional pathogenic mutations suggests that penetrance and phenotypic expression of C9ORF72 RE may depend on additional genetic risk factors

Original languageEnglish
JournalNeurobiology of Aging
Issue number10
Publication statusPublished - Oct 2012


  • Amyotrophic lateral sclerosis
  • C9ORF72
  • Frontotemporal dementia
  • Haplotype analysis
  • Mutation analysis
  • Repeat expansion

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Ageing
  • Developmental Biology
  • Geriatrics and Gerontology


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