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

Abstract

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.

Figure 1. Early and late onset somatic mutations.

In the human cell lineage, germline progenitor cells that produce the gametes (at the horizontal dashed line) are formed before the somatic cell lineages start dividing. The progenitor cells and their daughter cells for 4 somatic cell lines are shown. (A) Here a somatic mutation has occurred in a CNS progenitor cell, which is passed on to its daughter cells (red-filled circles) but which leaves the other cell lines intact. Comparing DNA from both the CNS and from white blood cells will reveal this somatic mutation. (B) The somatic mutation here has affected an early stem cell, so most or all of the somatic cell lines will contain the mutation. This mutation can be detected if one monozygous twin has a white blood cell mutation and the other does not.