The role of de novo mutations in the development of amyotrophic lateral sclerosis

Abstract

The genetic basis combined with the sporadic occurrence of amyotrophic lateral sclerosis (ALS) suggests a role of de novo mutations in disease pathogenesis. Previous studies provided some evidence for this hypothesis; however, results were conflicting: no genes with recurrent occurring de novo mutations were identified and different pathways were postulated. In this study, we analyzed whole-exome data from 82 new patient-parents trios and combined it with the datasets of all previously published ALS trios (173 trios in total). The per patient de novo rate was not higher than expected based on the general population (P = 0.40). We showed that these mutations are not part of the previously postulated pathways, and gene-gene interaction analysis found no enrichment of interacting genes in this group (P = 0.57). Also, we were able to show that the de novo mutations in ALS patients are located in genes already prone for de novo mutations (P < 1 × 10^-15 ). Although the individual effect of rare de novo mutations in specific genes could not be assessed, our results indicate that, in contrast to previous hypothesis, de novo mutations in general do not impose a major burden on ALS risk.

Keywords: ALS; amyotrophic lateral sclerosis; de novo mutations; disease pathway; motor neuron disease; trios.

FIGURE 1

Protein interaction network of genes with de novo mutations by DAPPLE. Interacting genes are connected by a line, color represents the origin of the genes, genes found to harbor de novo mutations in this and previous studies are represented in orange, genes with a known association with development of ALS are represented in blue. A: The connectivity of the de novo mutation genes in the total network is not higher than one would expect by chance (P = 0.57). B: Protein interaction network after addition of the 34 known ALS genes. Two larger networks can be identified: one centered around FUS and one around TUBA4A.The connectivity in the total network is not significant (P = 0.41)

FIGURE 2

Distribution of the genes with de novo mutations compared with all genes in the genome. Genes with de novo mutations are from the combined data from this study, the study by Chesi et al. (2013) and the study by Steinberg et al. (2015). A: Average de novo mutation rate (DNM rate) per base of the genes with de novo mutations (blue) compared with the GoNL de novo database distribution (red); in general, the genes with de novo mutations have a higher per-base mutation rate (P < 1.0 × 10⁻¹⁵). B: Gene size (in base pairs) of the genes with de novo mutations (blue) compared with gene size of all genes from the genome (red); the genes with de novo mutations are on the whole larger (P < 1 × 10⁻¹⁵). C: Probability of de novo mutations per gene (the product of de novo mutation rate per base and gene size, blue) compared with the GoNL de novo database distribution (red); the genes with de novo mutations have, in general, a higher probability of de novo mutations (P < 1.0 × 10⁻¹⁵)