1. The role of de novo mutations in the development of amyotrophic lateral sclerosis
- Author
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Nicola Ticozzi, Peter M. Andersen, Albert C. Ludolph, Antonia Ratti, Nicolai Marroquin, Jan H. Veldink, Frank P. Diekstra, John Landers, Federico Verde, Raymond D. Schellevis, Kevin P. Kenna, Vincenzo Silani, Barbara Castellotti, Bernard Muller, Cinzia Gellera, Viviana Pensato, Cinzia Tiloca, Peter Nürnberg, Christian Kubisch, Sara L. Pulit, Laurent C. Francioli, Perry T.C. van Doormaal, Janine Altmüller, Susanne Motameny, Joachim Wolf, Daniel J. Overste, Jochen H. Weishaupt, Leonard H. van den Berg, Annelot M. Dekker, Alexander E Volk, and Daniela Calini
- Subjects
0301 basic medicine ,Male ,Mutation rate ,medicine.medical_specialty ,Population ,Biology ,medicine.disease_cause ,Article ,03 medical and health sciences ,0302 clinical medicine ,Mutation Rate ,Databases, Genetic ,Protein Interaction Mapping ,Exome Sequencing ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Protein Interaction Maps ,Amyotrophic lateral sclerosis ,education ,Genetics (clinical) ,Exome sequencing ,Alleles ,Genetic Association Studies ,education.field_of_study ,Mutation ,C9orf72 Protein ,Whole Genome Sequencing ,Amyotrophic Lateral Sclerosis ,medicine.disease ,030104 developmental biology ,Disease Pathway ,Amino Acid Substitution ,Case-Control Studies ,Medical genetics ,Female ,030217 neurology & neurosurgery - 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.
- Published
- 2017