Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies
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Published:2020-01-29
Issue:1
Volume:8
Page:
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ISSN:2051-5960
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Container-title:Acta Neuropathologica Communications
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language:en
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Short-container-title:acta neuropathol commun
Author:
Orme Tatiana, Hernandez Dena, Ross Owen A., Kun-Rodrigues Celia, Darwent Lee, Shepherd Claire E., Parkkinen Laura, Ansorge Olaf, Clark Lorraine, Honig Lawrence S., Marder Karen, Lemstra Afina, Rogaeva Ekaterina, St. George-Hyslop Peter, Londos Elisabet, Zetterberg Henrik, Morgan Kevin, Troakes Claire, Al-Sarraj Safa, Lashley Tammaryn, Holton Janice, Compta Yaroslau, Van Deerlin Vivianna, Trojanowski John Q., Serrano Geidy E., Beach Thomas G., Lesage Suzanne, Galasko Douglas, Masliah Eliezer, Santana Isabel, Pastor Pau, Tienari Pentti J., Myllykangas Liisa, Oinas Minna, Revesz Tamas, Lees Andrew, Boeve Brad F., Petersen Ronald C., Ferman Tanis J., Escott-Price Valentina, Graff-Radford Neill, Cairns Nigel J., Morris John C., Pickering-Brown Stuart, Mann David, Halliday Glenda, Stone David J., Dickson Dennis W., Hardy John, Singleton Andrew, Guerreiro Rita, Bras JoseORCID
Abstract
AbstractDementia 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.
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology (clinical),Pathology and Forensic Medicine
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