Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS

Mariely DeJesus-Hernandez, Ian R. Mackenzie, Bradley F. Boeve, Adam L. Boxer, Matt Baker, Nicola J. Rutherford, Alexandra M. Nicholson, Ni Cole A. Finch, Heather Flynn, Jennifer Adamson, Naomi Kouri, Aleksandra Wojtas, Pheth Sengdy, Ging Yuek R. Hsiung, Anna Karydas, William W. Seeley, Keith A. Josephs, Giovanni Coppola, Daniel H. Geschwind, Zbigniew K. WszolekHoward Feldman, David S. Knopman, Ronald C. Petersen, Bruce L. Miller, Dennis W. Dickson, Kevin B. Boylan, Neill R. Graff-Radford, Rosa Rademakers

Research output: Contribution to journalArticlepeer-review

2845 Scopus citations


Several families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43-based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS.

Original languageEnglish (US)
Pages (from-to)245-256
Number of pages12
Issue number2
StatePublished - Oct 20 2011

ASJC Scopus subject areas

  • Neuroscience(all)


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