@article{775c4251795141989ca5c3013e701c6e,
title = "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 = "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",
author = "{van Doormaal}, {Perry T C} and Nicola Ticozzi and Weishaupt, {Jochen H} and Kenna, {Kevin P} and Diekstra, {Frank P} and Federico Verde and Andersen, {Peter M.} and Dekker, {Annelot M} and Cinzia Tiloca and Nicolai Marroquin and Overste, {Daniel J} and Viviana Pensato and Peter N{\"u}rnberg and Pulit, {Sara L} and Schellevis, {Raymond D.} and Daniela Calini and Janine Altm{\"u}ller and Francioli, {Laurent C} and Bernard Muller and Barbara Castellotti and Susanne Motameny and Antonia Ratti and Joachim Wolf and Cinzia Gellera and Ludolph, {Albert C} and {van den Berg}, {Leonard H} and Christian Kubisch and Landers, {John E} and Veldink, {Jan H} and Vincenzo Silani and Volk, {Alexander E}",
note = "Funding Information: We are indebted to all patients and their families for their participation in this study. The technical assistance of Marika Pusch, Ingrid Goebel, and Antje Knehr (Institute of Human Genetics, Medical Centre Hamburg-Eppendorf, Hamburg, Germany) is gratefully acknowledged. We furthermore thank the Regional Computing Center of the University of Cologne (RRZK) for providing computing time on the DFG-funded High Performance Computing (HPC) system CHEOPS as well as support for analyzing the German and Swedish samples. The authors declare that they have no conflict of interest. Funding Information: Contract grant sponsors: ALS Foundation Netherlands; European Community{\textquoteright}s Health Seventh Framework Programme (FP7/2007-2013); ZonMW under the frame of E-Rare-2; the ERA Net for Research on Rare Diseases (PYRAMID); EU Joint Programme–Neurodegenerative Disease Research (JPND) project (STRENGTH, SOPHIA); Medical Research Council and Economic and Social Research Council (UK); Health Research Board (Ireland); ZonMw (The Netherlands); Ministry of Health and Ministry of Education, University and Research (Italy); L{\textquoteright}Agence nationale pour la recherch{\'e} (France); The Netherlands Organisation for Health Research and Development (Vici scheme); AriSLA – Fondazione Italiana di Ricerca per la SLA (NOVALS 2012); {\textquoteleft}5 × 1000{\textquoteright} Healthcare Research of the Italian Ministry of Health; The Italian Ministry of Health (GR-2011-02347820 {\textquoteleft}IRisALS{\textquoteright}); Deutsche Forschungsgemeinschaft (DFG) (VO 2028/1-1); BMBF-funded German Network for motor neuron diseases (MND-NET); Charcot Foundation for ALS Research; Virtual Helmholtz Association; International Graduate School in Molecular Medicine Ulm (IGradU). Publisher Copyright: {\textcopyright} 2017 Wiley Periodicals, Inc.",
year = "2017",
month = nov,
doi = "10.1002/humu.23295",
language = "English",
volume = "38",
pages = "1534--1541",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "Wiley-Liss Inc.",
number = "11",
}