Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies
Abstract Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing...
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| Format: | Article |
| Language: | English |
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BMC
2020-01-01
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| Series: | Acta Neuropathologica Communications |
| Online Access: | https://doi.org/10.1186/s40478-020-0879-z |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Tatiana Orme Dena Hernandez Owen A. Ross Celia Kun-Rodrigues Lee Darwent Claire E. Shepherd Laura Parkkinen Olaf Ansorge Lorraine Clark Lawrence S. Honig Karen Marder Afina Lemstra Ekaterina Rogaeva Peter St. George-Hyslop Elisabet Londos Henrik Zetterberg Kevin Morgan Claire Troakes Safa Al-Sarraj Tammaryn Lashley Janice Holton Yaroslau Compta Vivianna Van Deerlin John Q. Trojanowski Geidy E. Serrano Thomas G. Beach Suzanne Lesage Douglas Galasko Eliezer Masliah Isabel Santana Pau Pastor Pentti J. Tienari Liisa Myllykangas Minna Oinas Tamas Revesz Andrew Lees Brad F. Boeve Ronald C. Petersen Tanis J. Ferman Valentina Escott-Price Neill Graff-Radford Nigel J. Cairns John C. Morris Stuart Pickering-Brown David Mann Glenda Halliday David J. Stone Dennis W. Dickson John Hardy Andrew Singleton Rita Guerreiro Jose Bras |
| spellingShingle |
Tatiana Orme Dena Hernandez Owen A. Ross Celia Kun-Rodrigues Lee Darwent Claire E. Shepherd Laura Parkkinen Olaf Ansorge Lorraine Clark Lawrence S. Honig Karen Marder Afina Lemstra Ekaterina Rogaeva Peter St. George-Hyslop Elisabet Londos Henrik Zetterberg Kevin Morgan Claire Troakes Safa Al-Sarraj Tammaryn Lashley Janice Holton Yaroslau Compta Vivianna Van Deerlin John Q. Trojanowski Geidy E. Serrano Thomas G. Beach Suzanne Lesage Douglas Galasko Eliezer Masliah Isabel Santana Pau Pastor Pentti J. Tienari Liisa Myllykangas Minna Oinas Tamas Revesz Andrew Lees Brad F. Boeve Ronald C. Petersen Tanis J. Ferman Valentina Escott-Price Neill Graff-Radford Nigel J. Cairns John C. Morris Stuart Pickering-Brown David Mann Glenda Halliday David J. Stone Dennis W. Dickson John Hardy Andrew Singleton Rita Guerreiro Jose Bras Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies Acta Neuropathologica Communications |
| author_facet |
Tatiana Orme Dena Hernandez Owen A. Ross Celia Kun-Rodrigues Lee Darwent Claire E. Shepherd Laura Parkkinen Olaf Ansorge Lorraine Clark Lawrence S. Honig Karen Marder Afina Lemstra Ekaterina Rogaeva Peter St. George-Hyslop Elisabet Londos Henrik Zetterberg Kevin Morgan Claire Troakes Safa Al-Sarraj Tammaryn Lashley Janice Holton Yaroslau Compta Vivianna Van Deerlin John Q. Trojanowski Geidy E. Serrano Thomas G. Beach Suzanne Lesage Douglas Galasko Eliezer Masliah Isabel Santana Pau Pastor Pentti J. Tienari Liisa Myllykangas Minna Oinas Tamas Revesz Andrew Lees Brad F. Boeve Ronald C. Petersen Tanis J. Ferman Valentina Escott-Price Neill Graff-Radford Nigel J. Cairns John C. Morris Stuart Pickering-Brown David Mann Glenda Halliday David J. Stone Dennis W. Dickson John Hardy Andrew Singleton Rita Guerreiro Jose Bras |
| author_sort |
Tatiana Orme |
| title |
Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies |
| title_short |
Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies |
| title_full |
Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies |
| title_fullStr |
Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies |
| title_full_unstemmed |
Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies |
| title_sort |
analysis of neurodegenerative disease-causing genes in dementia with lewy bodies |
| publisher |
BMC |
| series |
Acta Neuropathologica Communications |
| issn |
2051-5960 |
| publishDate |
2020-01-01 |
| description |
Abstract Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease. |
| url |
https://doi.org/10.1186/s40478-020-0879-z |
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doaj-eb7da7eb422d4a428e7652ae48f842e32021-01-31T16:18:32ZengBMCActa Neuropathologica Communications2051-59602020-01-018111110.1186/s40478-020-0879-zAnalysis of neurodegenerative disease-causing genes in dementia with Lewy bodiesTatiana Orme0Dena Hernandez1Owen A. Ross2Celia Kun-Rodrigues3Lee Darwent4Claire E. Shepherd5Laura Parkkinen6Olaf Ansorge7Lorraine Clark8Lawrence S. Honig9Karen Marder10Afina Lemstra11Ekaterina Rogaeva12Peter St. George-Hyslop13Elisabet Londos14Henrik Zetterberg15Kevin Morgan16Claire Troakes17Safa Al-Sarraj18Tammaryn Lashley19Janice Holton20Yaroslau Compta21Vivianna Van Deerlin22John Q. Trojanowski23Geidy E. Serrano24Thomas G. Beach25Suzanne Lesage26Douglas Galasko27Eliezer Masliah28Isabel Santana29Pau Pastor30Pentti J. Tienari31Liisa Myllykangas32Minna Oinas33Tamas Revesz34Andrew Lees35Brad F. Boeve36Ronald C. Petersen37Tanis J. Ferman38Valentina Escott-Price39Neill Graff-Radford40Nigel J. Cairns41John C. Morris42Stuart Pickering-Brown43David Mann44Glenda Halliday45David J. Stone46Dennis W. Dickson47John Hardy48Andrew Singleton49Rita Guerreiro50Jose Bras51UK Dementia Research Institute at UCL and Department of Molecular Neuroscience, Institute of Neurology, University College LondonLaboratory of Neurogenetics, National Institutes on Aging, NIHDepartment of Neuroscience, Mayo ClinicCenter for Neurodegenerative Science, Van Andel Research InstituteUK Dementia Research Institute at UCL and Department of Molecular Neuroscience, Institute of Neurology, University College LondonNeuroscience Research Australia, Sydney, Australia and School of Medical Sciences, Faculty of Medicine, University of New South WalesNuffield Department of Clinical Neurosciences, Oxford Parkinson’s Disease Centre, University of OxfordNuffield Department of Clinical Neurosciences, Oxford Parkinson’s Disease Centre, University of OxfordTaub Institute for Alzheimer Disease and the Aging Brain and Department of Pathology and Cell Biology and Neurology, Columbia University Medical CenterTaub Institute for Alzheimer Disease and the Aging Brain and Department of Pathology and Cell Biology and Neurology, Columbia University Medical CenterTaub Institute for Alzheimer Disease and the Aging Brain and Department of Pathology and Cell Biology and Neurology, Columbia University Medical CenterDepartment of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical CenterDepartment of Medicine, Tanz Centre for Research in Neurodegenerative Diseases, University of TorontoDepartment of Medicine, Tanz Centre for Research in Neurodegenerative Diseases, University of TorontoClinical Memory Research Unit, Institution of Clinical Sciences Malmö, Lund UniversityUK Dementia Research Institute at UCL and Department of Molecular Neuroscience, Institute of Neurology, University College LondonHuman Genetics, School of Life Sciences, University of NottinghamDepartment of Basic and Clinical Neuroscience and Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonDepartment of Basic and Clinical Neuroscience and Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonQueen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of NeurologyQueen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of NeurologyQueen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of NeurologyDepartment of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of PennsylvaniaDepartment of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of PennsylvaniaBanner Sun Health Research InstituteBanner Sun Health Research InstituteSorbonne Université, Université Pierre et Marie Curie-Paris 06, Inserm, Centre National de la Reserche Scientifique, and Institute du Cerveau et de la Moelle épinièreAssistance Publique Hôpitaux de Paris, Hôpital de la Salpêtrière, Département de Génétique et CytogénétiqueDivision of Neurosciences and Laboratory of Neurogenetics, National Institute on Aging/NIHNeurology Service, University of Coimbra HospitalMemory Unit, Department of Neurology, University Hospital Mutua de Terrassa, University of BarcelonaTranslational Immunology, Research Programs Unit, Department of Neurology, Helsinki University Hospital, University of HelsinkiDepartment of Pathology, University of Helsinki and HUSLAB, Helsinki University HospitalDepartment of Neuropathology and Neurosurgery, Helsinki University Hospital and University of HelsinkiQueen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of NeurologyQueen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of NeurologyNeurology Department, Mayo ClinicDepartment of Psychiatry and Department of Psychology, Mayo ClinicDepartment of Psychiatry and Department of Psychology, Mayo ClinicUK Dementia Research Institute at Cardiff and MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff UniversityDepartment of Neurology, Mayo ClinicDepartment of Neurology, Washington University School of MedicineDivision of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of ManchesterDivision of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of ManchesterDivision of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of ManchesterNeuroscience Research Australia, Sydney, Australia and School of Medical Sciences, Faculty of Medicine, University of New South WalesGenetics and Pharmacogenomics, Merck & Co., Inc.Department of Neuroscience, Mayo ClinicUK Dementia Research Institute at UCL and Department of Molecular Neuroscience, Institute of Neurology, University College LondonLaboratory of Neurogenetics, National Institutes on Aging, NIHCenter for Neurodegenerative Science, Van Andel Research InstituteCenter for Neurodegenerative Science, Van Andel Research InstituteAbstract Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.https://doi.org/10.1186/s40478-020-0879-z |