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Journal Articles Acta Neuropathologica Communications Year : 2020

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

Tatiana Orme
  • Function : Author
Dena Hernandez
  • Function : Author
Owen A Ross
  • Function : Author
Celia Kun-Rodrigues
  • Function : Author
Lee Darwent
  • Function : Author
Claire E Shepherd
  • Function : Author
Laura Parkkinen
  • Function : Author
Olaf Ansorge
  • Function : Author
Lorraine Clark
  • Function : Author
Lawrence S Honig
  • Function : Author
Karen Marder
  • Function : Author
Afina Lemstra
  • Function : Author
Ekaterina Rogaeva
  • Function : Author
Peter St. George-Hyslop
  • Function : Author
Elisabet Londos
  • Function : Author
Henrik Zetterberg
  • Function : Author
Kevin Morgan
  • Function : Author
Claire Troakes
  • Function : Author
Safa Al-Sarraj
  • Function : Author
Tammaryn Lashley
  • Function : Author
Janice Holton
  • Function : Author
Yaroslau Compta
  • Function : Author
Vivianna van Deerlin
  • Function : Author
John Q Trojanowski
  • Function : Author
Geidy E Serrano
  • Function : Author
Thomas G Beach
  • Function : Author
Douglas Galasko
  • Function : Author
Eliezer Masliah
  • Function : Author
Isabel Santana
  • Function : Author
Pau Pastor
  • Function : Author
Pentti J Tienari
  • Function : Author
Liisa Myllykangas
  • Function : Author
Minna Oinas
  • Function : Author
Tamas Revesz
  • Function : Author
Andrew Lees
  • Function : Author
Brad F Boeve
  • Function : Author
Ronald C Petersen
  • Function : Author
Tanis J Ferman
  • Function : Author
Valentina Escott-Price
  • Function : Author
Neill Graff-Radford
  • Function : Author
Nigel J Cairns
  • Function : Author
John C Morris
  • Function : Author
Stuart Pickering-Brown
  • Function : Author
David Mann
  • Function : Author
Glenda Halliday
  • Function : Author
David J Stone
  • Function : Author
Dennis W Dickson
  • Function : Author
John Hardy
  • Function : Author
Andrew Singleton
  • Function : Author
Rita Guerreiro
  • Function : Author
Jose Bras

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.
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Licence : CC BY - Attribution

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hal-04488775 , version 1 (04-03-2024)

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Tatiana Orme, Dena Hernandez, Owen A Ross, Celia Kun-Rodrigues, Lee Darwent, et al.. Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies. Acta Neuropathologica Communications, 2020, 8 (1), pp.5. ⟨10.1186/s40478-020-0879-z⟩. ⟨hal-04488775⟩
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