Screening a UK amyotrophic lateral sclerosis cohort provides evidence of multiple origins of the C9orf72 expansion

Pietro Fratta, James M. Polke, Jia Newcombe, Sarah Mizielinska, Tammaryn Lashley, Mark Poulter, Jon Beck, Elisavet Preza, Anny Devoy, Katie Sidle, Robin Howard, Andrea Malaspina, Richard W. Orrell, Jan Clarke, Ching Hua Lu, Kin Mok, Toby Collins, Maryam Shoaii, Tina Nanji, Selina WrayGary Adamson, Alan Pittman, Alan E. Renton, Bryan J. Traynor, Mary G. Sweeney, Tamas Revesz, Henry Houlden, Simon Mead, Adrian M. Isaacs, Elizabeth M.C. Fisher

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Although 0-30 hexanucleotide repeats are present in the general population, expansions >500 repeats are associated with C9ALS/FTD. Large C9ALS/FTD expansions share a common haplotype and whether these expansions derive from a single founder or occur more frequently on a predisposing haplotype is yet to be determined and is relevant to disease pathomechanisms. Furthermore, although cases carrying 50-200 repeats have been described, their role and the pathogenic threshold of the expansions remain to be identified and carry importance for diagnostics and genetic counseling. We present clinical and genetic data from a UK ALS cohort and report the detailed molecular study of an atypical somatically unstable expansion of 90 repeats. Our results across different tissues provide evidence for the pathogenicity of this repeat number by showing they can somatically expand in the central nervous system to the well characterized pathogenic range. Our results support the occurrence of multiple expansion events for C9ALS/FTD.

Original languageEnglish
Pages (from-to)546.e1-546.e7
JournalNeurobiology of Aging
Issue number1
StatePublished - 1 Jan 2015
Externally publishedYes


  • Amyotrophic lateral sclerosis
  • Frontotemporal dementia
  • Somatic instability


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