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Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Orme, Tatiana 
Hernandez, Dena 
Ross, Owen A 
Kun-Rodrigues, Celia 
Darwent, Lee 

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.

Description

Keywords

Aged, Aged, 80 and over, Cerebellum, Cohort Studies, Female, Frontal Lobe, Humans, Lewy Body Disease, Male, Mutation, Neurodegenerative Diseases, Exome Sequencing

Journal Title

Acta Neuropathol Commun

Conference Name

Journal ISSN

2051-5960
2051-5960

Volume Title

8

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MR/N026004/1)
Medical Research Council (MR/L023784/2)