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

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 & 32 others 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

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)5
Number of pages1
JournalActa Neuropathologica Communinications
Volume8
Issue number1
DOIs
Publication statusPublished - 29 Jan 2020

Cite this

Orme, T., Hernandez, D., Ross, O. A., Kun-Rodrigues, C., Darwent, L., Shepherd, C. E., ... Bras, J. (2020). Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies. Acta Neuropathologica Communinications, 8(1), 5. https://doi.org/10.1186/s40478-020-0879-z
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, Jose. / Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies. In: Acta Neuropathologica Communinications. 2020 ; Vol. 8, No. 1. pp. 5.
@article{9d55c0863dfd434b86f3a46847eabcbc,
title = "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 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.",
author = "Tatiana Orme and Dena Hernandez and Ross, {Owen A.} and Celia Kun-Rodrigues and Lee Darwent and Shepherd, {Claire E.} and Laura Parkkinen and Olaf Ansorge and Lorraine Clark and Honig, {Lawrence S.} and Karen Marder and Afina Lemstra and Ekaterina Rogaeva and {St George-Hyslop}, Peter and Elisabet Londos and Henrik Zetterberg and Kevin Morgan and Claire Troakes and Safa Al-Sarraj and Tammaryn Lashley and Janice Holton and Yaroslau Compta and {Van Deerlin}, Vivianna and Trojanowski, {John Q.} and Serrano, {Geidy E.} and Beach, {Thomas G.} and Suzanne Lesage and Douglas Galasko and Eliezer Masliah and Isabel Santana and Pau Pastor and Tienari, {Pentti J.} and Liisa Myllykangas and Minna Oinas and Tamas Revesz and Andrew Lees and Boeve, {Brad F.} and Petersen, {Ronald C.} and Ferman, {Tanis J.} and Valentina Escott-Price and Neill Graff-Radford and Cairns, {Nigel J.} and Morris, {John C.} and Stuart Pickering-Brown and David Mann and Glenda Halliday and Stone, {David J.} and Dickson, {Dennis W.} and John Hardy and Andrew Singleton and Rita Guerreiro and Jose Bras",
year = "2020",
month = "1",
day = "29",
doi = "10.1186/s40478-020-0879-z",
language = "English",
volume = "8",
pages = "5",
journal = "Acta Neuropathologica Communinications",
issn = "2051-5960",
publisher = "BioMed Central",
number = "1",

}

Orme, T, Hernandez, D, Ross, OA, Kun-Rodrigues, C, Darwent, L, Shepherd, CE, Parkkinen, L, Ansorge, O, Clark, L, Honig, LS, Marder, K, Lemstra, A, Rogaeva, E, St George-Hyslop, P, Londos, E, Zetterberg, H, Morgan, K, Troakes, C, Al-Sarraj, S, Lashley, T, Holton, J, Compta, Y, Van Deerlin, V, Trojanowski, JQ, Serrano, GE, Beach, TG, Lesage, S, Galasko, D, Masliah, E, Santana, I, Pastor, P, Tienari, PJ, Myllykangas, L, Oinas, M, Revesz, T, Lees, A, Boeve, BF, Petersen, RC, Ferman, TJ, Escott-Price, V, Graff-Radford, N, Cairns, NJ, Morris, JC, Pickering-Brown, S, Mann, D, Halliday, G, Stone, DJ, Dickson, DW, Hardy, J, Singleton, A, Guerreiro, R & Bras, J 2020, 'Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies' Acta Neuropathologica Communinications, vol. 8, no. 1, pp. 5. https://doi.org/10.1186/s40478-020-0879-z

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

In: Acta Neuropathologica Communinications, Vol. 8, No. 1, 29.01.2020, p. 5.

Research output: Contribution to journalArticleAcademicpeer-review

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 - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85078689290&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/31996268

U2 - 10.1186/s40478-020-0879-z

DO - 10.1186/s40478-020-0879-z

M3 - Article

VL - 8

SP - 5

JO - Acta Neuropathologica Communinications

JF - Acta Neuropathologica Communinications

SN - 2051-5960

IS - 1

ER -