TY - JOUR
T1 - Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies
AU - Orme, Tatiana
AU - Hernandez, Dena
AU - Ross, Owen A.
AU - Kun-Rodrigues, Celia
AU - Darwent, Lee
AU - Shepherd, Claire E.
AU - Parkkinen, Laura
AU - Ansorge, Olaf
AU - Clark, Lorraine
AU - Honig, Lawrence S.
AU - Marder, Karen
AU - Lemstra, Afina
AU - Rogaeva, Ekaterina
AU - St. George-Hyslop, Peter
AU - Londos, Elisabet
AU - Zetterberg, Henrik
AU - Morgan, Kevin
AU - Troakes, Claire
AU - Al-Sarraj, Safa
AU - Lashley, Tammaryn
AU - Holton, Janice
AU - Compta, Yaroslau
AU - Van Deerlin, Vivianna
AU - Trojanowski, John Q.
AU - Serrano, Geidy E.
AU - Beach, Thomas G.
AU - Lesage, Suzanne
AU - Galasko, Douglas
AU - Masliah, Eliezer
AU - Santana, Isabel
AU - Pastor, Pau
AU - Tienari, Pentti J.
AU - Myllykangas, Liisa
AU - Oinas, Minna
AU - Revesz, Tamas
AU - Lees, Andrew
AU - Boeve, Brad F.
AU - Petersen, Ronald C.
AU - Ferman, Tanis J.
AU - Escott-Price, Valentina
AU - Graff-Radford, Neill
AU - Cairns, Nigel J.
AU - Morris, John C.
AU - Pickering-Brown, Stuart
AU - Mann, David
AU - Halliday, Glenda
AU - Stone, David J.
AU - Dickson, Dennis W.
AU - Hardy, John
AU - Singleton, Andrew
AU - Guerreiro, Rita
AU - Bras, Jose
PY - 2020/1/29
Y1 - 2020/1/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85078689290&partnerID=8YFLogxK
U2 - 10.1186/s40478-020-0879-z
DO - 10.1186/s40478-020-0879-z
M3 - Article
C2 - 31996268
AN - SCOPUS:85078689290
SN - 2051-5960
VL - 8
JO - Acta Neuropathologica Communications
JF - Acta Neuropathologica Communications
IS - 1
M1 - 5
ER -