Can ALS-associated C9orf72 repeat expansions be diagnosed on a blood DNA test alone?

PLoS One. 2013 Jul 19;8(7):e70007. doi: 10.1371/journal.pone.0070007. Print 2013.


Gene mutations that preferentially affect the CNS have been implicated in a number of neurological disorders. This leads to the possibility that a disease-causing mutation present only in CNS tissues could be missed if it were tested in a blood DNA sample only. The commonest mutation in amyotrophic lateral sclerosis (ALS) is an expansion of the hexanucleotide repeats of C9orf72. To find out if CNS-specific mutations of this gene could cause some cases of ALS we looked for differences in the size of C9orf72 repeats between DNA from the CNS and from white blood cells (WBCs) of 38 sporadic ALS patients, using a repeat-primed PCR screening test. We also looked for differences in C9orf72 repeats in WBC DNA from 6 ALS-discordant and 1 ALS-concordant monozygotic twins. Abnormally expanded C9orf72 repeats were found in 13% of the ALS CNS samples, as well as in their paired WBC DNA. The 87% of ALS CNS samples with normal-sized C9orf72 repeats had the same number of repeats in paired WBC samples. All ALS-discordant twins had the same normal numbers of WBC C9orf72 repeats. Although previous work suggests some tissue mosaicism in C9orf72 repeat size is probably present, this study indicates that this is not likely to be of sufficient magnitude to result in a normal C9orf72 repeat length in blood but an abnormally expanded repeat length in the CNS. This suggests that a blood DNA test alone will usually be sufficient to make a diagnosis of C9orf72 repeat-related ALS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Amyotrophic Lateral Sclerosis / diagnosis*
  • Amyotrophic Lateral Sclerosis / genetics*
  • C9orf72 Protein
  • Case-Control Studies
  • Cerebral Cortex / metabolism
  • DNA Repeat Expansion*
  • Female
  • Humans
  • Leukocytes / metabolism
  • Male
  • Middle Aged
  • Proteins / genetics*
  • Spinal Cord / metabolism
  • Twins, Monozygotic / genetics


  • C9orf72 Protein
  • C9orf72 protein, human
  • Proteins

Grant support

This work was supported by the MND Research Institute of Australia and the Aimee Stacey and Burnett bequests. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.