Genetic reports abstractNegative resultsLength of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype
Introduction
Clinical, genetic, and histopathological evidence suggests that similar pathological processes underlie amyotrophic lateral sclerosis (ALS) and some types of frontotemporal dementia (FTD); a notion which was reinforced by the discovery of GGGGCC repeat expansions in a noncoding region of Chromosome 9 open reading frame 72 (C9ORF72) (DeJesus-Hernandez et al., 2011; Renton et al., 2011). In this study, we focused on the length of the normal alleles of the C9ORF72 repeat in patients with or without repeat expansions, to determine whether the length of this “wild type” allele has any effect on the disease phenotype or age of disease onset in FTD and ALS patients. We hypothesized that longer GGGGCC repeats within the normal range, suggested to be <30 repeats (Cerami et al., 2012), in C9ORF72 would lead to an increase in disease risk or an earlier age at disease onset.
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Methods
Our study cohort consisted of 3179 individuals, 1735 patients (580 FTD, 995 ALS, and 160 FTD-ALS) and 1444 controls. Demographic information on these individuals is summarized in Supplementary Table 1. All patients and controls were genotyped for the C9ORF72 GGGGCC repeat using our previously published 2-step protocol (DeJesus-Hernandez et al., 2011). Statistical analyses were performed using R Statistical Software v2.11.0 (open source software, available at http://cran.r-project.org). To
Results
We identified 211 patients (59 FTD, 94 ALS, and 58 FTD-ALS) carrying a pathogenic GGGGCC repeat expansion. The maximum number of repeats within the normal range that we identified was 25 in a patient and 23 in a control. For a complete overview of the allele counts in patients and controls see Supplementary Tables 2 and 3. A graphical representation of the number of repeats on the normal alleles in nonmutation carriers in each of the disease groups compared with controls is provided in
Discussion
This is the first study to examine whether normal—unexpanded—C9ORF72 GGGGCC hexanucleotide repeat alleles, play a role in disease presentation or affect age at disease onset in patients with or without a pathogenic C9ORF72 repeat expansion. C9ORF72 mutation carriers can present with FTD, ALS, or a combination of both diseases and the age at which first symptoms appear varies widely. However, using our large collection of 211 C9ORF72 mutation carriers, we did not observe any evidence for a role
Disclosure statement
RR and MD-J have a patent on the discovery of the hexanucleotide repeat expansion in C9ORF72. All other authors report no conflict of interest.
Acknowledgements
We would like to thank all the patients and their families who took part in this study. ALS samples from the NINDS Human Genetics Resource Center DNA and Cell Line Repository (ccr.coriell.org/ninds) were included in this study. This work was supported by the ALS Therapy Alliance, the Consortium for Frontotemporal Dementia (CFR), The Winspear Family Center for Research on the Neuropathology of Alzheimer Disease, the McCune Foundation, NIH grants R01 NS065782, P50 AG16574, P50 NS072187-01S2 and
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