C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies

Neurology. 2014 Jan 28;82(4):292-9. doi: 10.1212/WNL.0000000000000061. Epub 2013 Dec 20.


Objective: In many cases where Huntington disease (HD) is suspected, the genetic test for HD is negative: these are known as HD phenocopies. A repeat expansion in the C9orf72 gene has recently been identified as a major cause of familial and sporadic frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Our objective was to determine whether this mutation causes HD phenocopies.

Methods: A cohort of 514 HD phenocopy patients were analyzed for the C9orf72 expansion using repeat primed PCR. In cases where the expansion was found, Southern hybridization was performed to determine expansion size. Clinical case notes were reviewed to determine the phenotype of expansion-positive cases.

Results: Ten subjects (1.95%) had the expansion, making it the most common identified genetic cause of HD phenocopy presentations. The size of expansion was not significantly different from that associated with other clinical presentations of C9orf72 expanded cases. The C9orf72 expansion-positive subjects were characterized by the presence of movement disorders, including dystonia, chorea, myoclonus, tremor, and rigidity. Furthermore, the age at onset in this cohort was lower than previously reported for subjects with the C9orf72 expansion and included one case with pediatric onset.

Discussion: This study extends the known phenotype of the C9orf72 expansion in both age at onset and movement disorder symptoms. We propose a revised clinico-genetic algorithm for the investigation of HD phenocopy patients based on these data.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • C9orf72 Protein
  • Child
  • Cognition Disorders / etiology
  • Cognition Disorders / genetics
  • Cohort Studies
  • DNA Mutational Analysis
  • DNA Repeat Expansion / genetics*
  • Female
  • Humans
  • Huntington Disease / complications
  • Huntington Disease / genetics*
  • Magnetic Resonance Imaging
  • Male
  • Mental Status Schedule
  • Middle Aged
  • Phenotype
  • Proteins / genetics*
  • Severity of Illness Index
  • Young Adult


  • C9orf72 Protein
  • C9orf72 protein, human
  • Proteins