Investigation of C9orf72 in 4 neurodegenerative disorders

Zhengrui Xi, Lorne Zinman, Yakov Grinberg, Danielle Moreno, Christine Sato, Juan M. Bilbao, Mahdi Ghani, Isabel Hernańdez, Agustiń Ruiz, Mercè Boada, Francisco J. Morón, Anthony E. Lang, Connie Marras, Amalia Bruni, Rosanna Colao, Raffaele G. Maletta, Gianfranco Puccio, Innocenzo Rainero, Lorenzo Pinessi, Daniela GalimbertiKaren E. Morrison, Catriona Moorby, Joanne D. Stockton, Mario Masellis, Sandra E. Black, Lili Naz Hazrati, Yan Liang, Jan Van Haersma De With, Luis Fornazzari, Roque Villagra, Ricardo Rojas-Garcia, Jordi Clarimoń, Richard Mayeux, Janice Robertson, Peter St George-Hyslop, Ekaterina Rogaeva

Research output: Contribution to journalArticlepeer-review


Objective: To estimate the allele frequency of C9orf72 (G4C 2) repeats in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer disease (AD), and Parkinson disease (PD). Design: The number of repeats was estimated by a 2-step genotyping strategy. For expansion carriers, we sequenced the repeat flanking regions and obtained APOE genotypes and MAPT H1/H2 haplotypes. Setting: Hospitals specializing in neurodegenerative disorders. Subjects: We analyzed 520 patients with FTLD, 389 patients with ALS, 424 patients with AD, 289 patients with PD, 602 controls, 18 families, and 29 patients with PD with the LRRK2 G2019S mutation. Main Outcome Measure: The expansion frequency. Results: Based on a prior cutoff (>30 repeats), the expansion was detected in 9.3% of patients with ALS, 5.2% of patients with FTLD, and 0.7% of patients with PD but not in controls or patients with AD. It was significantly associated with family history of ALS or FTLD and age at onset of FTLD. Phenotype variation (ALS vs FTLD) was not associated with MAPT, APOE, or variability in the repeat flanking regions. Two patients with PD were carriers of 39 and 32 repeats with questionable pathological significance, since the 39-repeat allele does not segregate with PD. No expansion or intermediate alleles (20-29 repeats) were found among the G2019S carriers and AD cases with TAR DNA-binding protein 43-positive inclusions. Surprisingly, the frequency of the 10-repeat allele was marginally increased in all 4 neurodegenerative diseases compared with controls, indicating the presence of an unknown risk variation in the C9orf72 locus. Conclusions: The C9orf72 expansion is a common cause of ALS and FTLD, but not of AD or PD. Our study raises concern about a reliable cutoff for the pathological repeat number, which is important in the utility of genetic screening.

Original languageEnglish
Pages (from-to)1583-1590
Number of pages8
JournalArchives of Neurology
Issue number12
Publication statusPublished - Dec 2012

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)


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