C9ORF72 hexanucleotide expansions of 20-22 repeats are associated with frontotemporal deterioration

Neurology. 2013 Jan 22;80(4):366-70. doi: 10.1212/WNL.0b013e31827f08ea. Epub 2013 Jan 2.


Objective: Expansions of more than 30 hexanucleotide repetitions in the C9ORF72 gene are a common cause of frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). However, the range of 20-30 repetitions is rarely found and still has unclear significance. A screening of our cohort of cases with FTD (n = 109) revealed 4 mutation carriers (>30 repetitions) but also 5 probands with 20-22 confirmed repetitions. This study explored the possible pathogenic correlation of the 20-22 repeats expansion (short expansion).

Methods: Comparison of clinical phenotypes between cases with long vs short expansions; search for segregation in the families of probands with short expansion; analysis of the presence of the common founder haplotype, described for expansions >30 repeats, in the cases having the short expansion; and analysis of the distribution of hexanucleotide repeat alleles in a control population.

Results: No different patterns were found in the clinical phenotype or aggressiveness of the disease when comparing cases with long or short expansions. Cases in both groups had psychiatric symptoms during 1-3 decades before evolving insidiously to cognitive deterioration. The study of the families with short expansion showed clear segregation of the 20-22 repeats allele with the disease. Moreover, this 20-22 repeats allele was associated in all cases with the pathogenic founder haplotype. None of 216 controls had alleles with more than 14 repetitions.

Conclusions: Description of these families suggests that short C9ORF72 hexanucleotide expansions are also related to frontotemporal cognitive deterioration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • C9orf72 Protein
  • Cohort Studies
  • DNA Repeat Expansion / genetics*
  • Female
  • Frontotemporal Dementia / genetics*
  • Frontotemporal Dementia / pathology*
  • Haplotypes
  • Humans
  • Male
  • Middle Aged
  • Pedigree
  • Phenotype
  • Proteins / genetics*
  • Severity of Illness Index
  • Siblings


  • C9orf72 Protein
  • C9orf72 protein, human
  • Proteins