The role of de novo mutations in the development of amyotrophic lateral sclerosis
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 mutat...
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| Published in | Human mutation Vol. 38; no. 11; pp. 1534 - 1541 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
John Wiley & Sons, Inc
01.11.2017
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| Subjects | |
| Online Access | Get full text |
| ISSN | 1059-7794 1098-1004 1098-1004 |
| DOI | 10.1002/humu.23295 |
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| 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.
In this study we analyzed whole‐exome data from 82 new patient‐parents trios and combined it with the datasets of all previously published amyotrophic lateral sclerosis trios (173 trios in total). Using multiple analysis methods, we show that de novo mutations do not impose a major burden on amyotrophic lateral sclerosis risk. |
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| AbstractList | 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 x 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. 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.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. 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. 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 ). 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. 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. In this study we analyzed whole‐exome data from 82 new patient‐parents trios and combined it with the datasets of all previously published amyotrophic lateral sclerosis trios (173 trios in total). Using multiple analysis methods, we show that de novo mutations do not impose a major burden on amyotrophic lateral sclerosis risk. 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. |
| Author | Overste, Daniel J. Pulit, Sara L. Veldink, Jan H. Schellevis, Raymond D. Andersen, Peter M. Ludolph, Albert C. Ratti, Antonia Castellotti, Barbara Calini, Daniela Altmüller, Janine Wolf, Joachim Gellera, Cinzia Motameny, Susanne Muller, Bernard Francioli, Laurent C. Kubisch, Christian Doormaal, Perry T.C. Verde, Federico Volk, Alexander E. Nürnberg, Peter Marroquin, Nicolai Diekstra, Frank P. Kenna, Kevin Tiloca, Cinzia Weishaupt, Jochen H. Pensato, Viviana Landers, John E. den Berg, Leonard H. Ticozzi, Nicola Silani, Vincenzo Dekker, Annelot M. |
| AuthorAffiliation | 3 Department of Pathophysiology and Transplantation, ‘Dino Ferrari’ Center-Università degli Studi di Milano, Milan, Italy 10 Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany 6 Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden 14 Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 5 Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 7 Institute of Human Genetics, University of Ulm, Ulm, Germany 4 Department of Neurology, University of Ulm, Ulm, Germany 13 Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 1 Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands 12 Institute of Human Genetics, University of Cologne, Cologne, Germany 15 Project MinE Foundation, Rotterdam, The Netherlands 17 Institute of Huma |
| AuthorAffiliation_xml | – name: 3 Department of Pathophysiology and Transplantation, ‘Dino Ferrari’ Center-Università degli Studi di Milano, Milan, Italy – name: 8 Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’, Milan, Italy – name: 13 Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts – name: 12 Institute of Human Genetics, University of Cologne, Cologne, Germany – name: 9 Cologne Center for Genomics, University of Cologne, Cologne, Germany – name: 4 Department of Neurology, University of Ulm, Ulm, Germany – name: 2 Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy – name: 11 Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands – name: 7 Institute of Human Genetics, University of Ulm, Ulm, Germany – name: 16 Department of Neurology, Diakonissenkrankenhaus Mannheim, Mannheim, Germany – name: 10 Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany – name: 6 Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden – name: 15 Project MinE Foundation, Rotterdam, The Netherlands – name: 17 Institute of Human Genetics, Medical Centre Hamburg-Eppendorf, Hamburg, Germany – name: 14 Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts – name: 1 Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands – name: 5 Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts |
| Author_xml | – sequence: 1 givenname: Perry T.C. orcidid: 0000-0001-8047-0288 surname: Doormaal fullname: Doormaal, Perry T.C. email: p.vandoormaal@umcutrecht.nl organization: University Medical Center Utrecht – sequence: 2 givenname: Nicola surname: Ticozzi fullname: Ticozzi, Nicola organization: ‘Dino Ferrari’ Center‐Università degli Studi di Milano – sequence: 3 givenname: Jochen H. surname: Weishaupt fullname: Weishaupt, Jochen H. organization: University of Ulm – sequence: 4 givenname: Kevin surname: Kenna fullname: Kenna, Kevin organization: University of Massachusetts Medical School – sequence: 5 givenname: Frank P. surname: Diekstra fullname: Diekstra, Frank P. organization: University Medical Center Utrecht – sequence: 6 givenname: Federico surname: Verde fullname: Verde, Federico organization: ‘Dino Ferrari’ Center‐Università degli Studi di Milano – sequence: 7 givenname: Peter M. surname: Andersen fullname: Andersen, Peter M. organization: Umeå University – sequence: 8 givenname: Annelot M. surname: Dekker fullname: Dekker, Annelot M. organization: University Medical Center Utrecht – sequence: 9 givenname: Cinzia surname: Tiloca fullname: Tiloca, Cinzia organization: IRCCS Istituto Auxologico Italiano – sequence: 10 givenname: Nicolai surname: Marroquin fullname: Marroquin, Nicolai organization: University of Ulm – sequence: 11 givenname: Daniel J. surname: Overste fullname: Overste, Daniel J. organization: University Medical Center Utrecht – sequence: 12 givenname: Viviana surname: Pensato fullname: Pensato, Viviana organization: Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’ – sequence: 13 givenname: Peter surname: Nürnberg fullname: Nürnberg, Peter organization: University of Cologne – sequence: 14 givenname: Sara L. surname: Pulit fullname: Pulit, Sara L. organization: University Medical Center Utrecht – sequence: 15 givenname: Raymond D. surname: Schellevis fullname: Schellevis, Raymond D. organization: University Medical Center Utrecht – sequence: 16 givenname: Daniela surname: Calini fullname: Calini, Daniela organization: IRCCS Istituto Auxologico Italiano – sequence: 17 givenname: Janine surname: Altmüller fullname: Altmüller, Janine organization: University of Cologne – sequence: 18 givenname: Laurent C. surname: Francioli fullname: Francioli, Laurent C. organization: Broad Institute of Harvard and Massachusetts Institute of Technology – sequence: 19 givenname: Bernard surname: Muller fullname: Muller, Bernard organization: Project MinE Foundation – sequence: 20 givenname: Barbara surname: Castellotti fullname: Castellotti, Barbara organization: Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’ – sequence: 21 givenname: Susanne surname: Motameny fullname: Motameny, Susanne organization: University of Cologne – sequence: 22 givenname: Antonia surname: Ratti fullname: Ratti, Antonia organization: ‘Dino Ferrari’ Center‐Università degli Studi di Milano – sequence: 23 givenname: Joachim surname: Wolf fullname: Wolf, Joachim organization: Diakonissenkrankenhaus Mannheim – sequence: 24 givenname: Cinzia surname: Gellera fullname: Gellera, Cinzia organization: Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’ – sequence: 25 givenname: Albert C. surname: Ludolph fullname: Ludolph, Albert C. organization: University of Ulm – sequence: 26 givenname: Leonard H. surname: den Berg fullname: den Berg, Leonard H. organization: University Medical Center Utrecht – sequence: 27 givenname: Christian surname: Kubisch fullname: Kubisch, Christian organization: Medical Centre Hamburg‐Eppendorf – sequence: 28 givenname: John E. surname: Landers fullname: Landers, John E. organization: University of Massachusetts Medical School – sequence: 29 givenname: Jan H. surname: Veldink fullname: Veldink, Jan H. organization: University Medical Center Utrecht – sequence: 30 givenname: Vincenzo surname: Silani fullname: Silani, Vincenzo organization: ‘Dino Ferrari’ Center‐Università degli Studi di Milano – sequence: 31 givenname: Alexander E. surname: Volk fullname: Volk, Alexander E. organization: Medical Centre Hamburg‐Eppendorf |
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| Keywords | ALS disease pathway motor neuron disease amyotrophic lateral sclerosis de novo mutations trios |
| Language | English |
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| Notes | Contract grant sponsors: ALS Foundation Netherlands; European Community'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'Agence nationale pour la recherché (France); The Netherlands Organisation for Health Research and Development (Vici scheme); AriSLA – Fondazione Italiana di Ricerca per la SLA (NOVALS 2012); ‘5 × 1000’ Healthcare Research of the Italian Ministry of Health; The Italian Ministry of Health (GR‐2011‐02347820 ‘IRisALS’); 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). Perry T.C. van Doormaal, Nicola Ticozzi, and Jochen H. Weishaupt contributed equally to this work. Communicated by Christine Van Broeckhoven John E. Landers, Jan H. Veldink, Vincenzo Silani, and Alexander E. Volk are senior coauthors. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 |
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| Snippet | The genetic basis combined with the sporadic occurrence of amyotrophic lateral sclerosis (ALS) suggests a role of de novo mutations in disease pathogenesis.... |
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| SubjectTerms | Alleles ALS Amino Acid Substitution Amyotrophic lateral sclerosis Amyotrophic Lateral Sclerosis - genetics Amyotrophic Lateral Sclerosis - metabolism C9orf72 Protein - genetics Case-Control Studies Data processing Databases, Genetic de novo mutations disease pathway Female Genes Genetic Association Studies Genetic Predisposition to Disease Humans Hypotheses Male motor neuron disease Motor neurone disease Mutation Mutation Rate Protein Interaction Mapping Protein Interaction Maps trios Whole Exome Sequencing Whole Genome Sequencing |
| Title | The role of de novo mutations in the development of amyotrophic lateral sclerosis |
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