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

Perry T C van Doormaal, Nicola Ticozzi, Jochen H Weishaupt, Kevin P Kenna, Frank P Diekstra, Federico Verde, Peter M. Andersen, Annelot M Dekker, Cinzia Tiloca, Nicolai Marroquin, Daniel J Overste, Viviana Pensato, Peter Nürnberg, Sara L Pulit, Raymond D. Schellevis, Daniela Calini, Janine Altmüller, Laurent C Francioli, Bernard Muller, Barbara CastellottiSusanne Motameny, Antonia Ratti, Joachim Wolf, Cinzia Gellera, Albert C Ludolph, Leonard H van den Berg, Christian Kubisch, John E Landers, Jan H Veldink, Vincenzo Silani, Alexander E Volk

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)1534-1541
Number of pages8
JournalHuman Mutation
Volume38
Issue number11
Early online date17 Jul 2017
DOIs
Publication statusPublished - Nov 2017

Keywords

  • Journal Article
  • motor neuron disease
  • de novo mutations
  • trios
  • ALS
  • disease pathway
  • amyotrophic lateral sclerosis
  • C9orf72 Protein/genetics
  • Genetic Predisposition to Disease
  • Genetic Association Studies
  • Humans
  • Databases, Genetic
  • Male
  • Mutation Rate
  • Amyotrophic Lateral Sclerosis/genetics
  • Case-Control Studies
  • Protein Interaction Mapping
  • Protein Interaction Maps
  • Whole Exome Sequencing
  • Whole Genome Sequencing
  • Alleles
  • Female
  • Mutation
  • Amino Acid Substitution

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