Unravelling the clinical spectrum and the role of repeat length in C9ORF72 repeat expansions

Emma L. Van Der Ende, Jazmyne L. Jackson, Adrianna White, Harro Seelaar, Marka Van Blitterswijk, John C. Van Swieten

Research output: Contribution to journalReview articlepeer-review


Since the discovery of the C9orf72 repeat expansion as the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis, it has increasingly been associated with a wider spectrum of phenotypes, including other types of dementia, movement disorders, psychiatric symptoms and slowly progressive FTD. Prompt recognition of patients with C9orf72-associated diseases is essential in light of upcoming clinical trials. The striking clinical heterogeneity associated with C9orf72 repeat expansions remains largely unexplained. In contrast to other repeat expansion disorders, evidence for an effect of repeat length on phenotype is inconclusive. Patients with C9orf72-associated diseases typically have very long repeat expansions, containing hundreds to thousands of GGGGCC-repeats, but smaller expansions might also have clinical significance. The exact threshold at which repeat expansions lead to neurodegeneration is unknown, and discordant cut-offs between laboratories pose a challenge for genetic counselling. Accurate and large-scale measurement of repeat expansions has been severely hindered by technical difficulties in sizing long expansions and by variable repeat lengths across and within tissues. Novel long-read sequencing approaches have produced promising results and open up avenues to further investigate this enthralling repeat expansion, elucidating whether its length, purity, and methylation pattern might modulate clinical features of C9orf72-related diseases.

Original languageEnglish (US)
Pages (from-to)502-509
Number of pages8
JournalJournal of Neurology, Neurosurgery and Psychiatry
Issue number5
StatePublished - May 1 2021


  • ALS
  • C9ORF72
  • frontotemporal dementia

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology
  • Psychiatry and Mental health


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