Clinical impact of whole-genome sequencing in patients with early-onset dementia.

Huq, AJ; Thompson, B; Bennett, MF; Bournazos, A; Bommireddipalli, S; Gorelik, A; Schultz, J; Sexton, A; Purvis, R; West, K; Cotter, M; Valente, G; Hughes, A; Riaz, M; Walsh, M; Farrand, S; Loi, SM; Kilpatrick, T; Brodtmann, A; Darby, D; Eratne, D; Walterfang, M; Delatycki, MB; Storey, E; Fahey, M; Cooper, S; Lacaze, P; Masters, CL; Velakoulis, D; Bahlo, M; James, PA; Winship, I

Clinical impact of whole-genome sequencing in patients with early-onset dementia.

Huq, AJ Thompson, B Bennett, MF Bournazos, A Bommireddipalli, S Gorelik, A Schultz, J Sexton, A

Purvis, R West, K Cotter, M Valente, G Hughes, A Riaz, M Walsh, M Farrand, S Loi, SM Kilpatrick, T Brodtmann, A Darby, D Eratne, D Walterfang, M Delatycki, MB Storey, E Fahey, M Cooper, S Lacaze, P Masters, CL Velakoulis, D Bahlo, M James, PA Winship, I

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Publisher:: BMJ
Publication Type:: Journal Article
Citation:: J Neurol Neurosurg Psychiatry, 2022, 93, (11), pp. jnnp-2021-328146
Issue Date:: 2022-07-29

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Field	Value	Language
dc.contributor.author	Huq, AJ
dc.contributor.author	Thompson, B
dc.contributor.author	Bennett, MF
dc.contributor.author	Bournazos, A
dc.contributor.author	Bommireddipalli, S
dc.contributor.author	Gorelik, A
dc.contributor.author	Schultz, J
dc.contributor.author	Sexton, A https://orcid.org/0000-0001-8749-1639
dc.contributor.author	Purvis, R
dc.contributor.author	West, K
dc.contributor.author	Cotter, M
dc.contributor.author	Valente, G
dc.contributor.author	Hughes, A
dc.contributor.author	Riaz, M
dc.contributor.author	Walsh, M
dc.contributor.author	Farrand, S
dc.contributor.author	Loi, SM
dc.contributor.author	Kilpatrick, T
dc.contributor.author	Brodtmann, A
dc.contributor.author	Darby, D
dc.contributor.author	Eratne, D
dc.contributor.author	Walterfang, M
dc.contributor.author	Delatycki, MB
dc.contributor.author	Storey, E
dc.contributor.author	Fahey, M
dc.contributor.author	Cooper, S
dc.contributor.author	Lacaze, P
dc.contributor.author	Masters, CL
dc.contributor.author	Velakoulis, D
dc.contributor.author	Bahlo, M
dc.contributor.author	James, PA
dc.contributor.author	Winship, I
dc.date.accessioned	2023-04-04T01:05:45Z
dc.date.available	2022-06-07
dc.date.available	2023-04-04T01:05:45Z
dc.date.issued	2022-07-29
dc.identifier.citation	J Neurol Neurosurg Psychiatry, 2022, 93, (11), pp. jnnp-2021-328146
dc.identifier.issn	0022-3050
dc.identifier.issn	1468-330X
dc.identifier.uri	http://hdl.handle.net/10453/169094
dc.description.abstract	BACKGROUND: In the clinical setting, identification of the genetic cause in patients with early-onset dementia (EOD) is challenging due to multiple types of genetic tests required to arrive at a diagnosis. Whole-genome sequencing (WGS) has the potential to serve as a single diagnostic platform, due to its superior ability to detect common, rare and structural genetic variation. METHODS: WGS analysis was performed in 50 patients with EOD. Point mutations, small insertions/deletions, as well as structural variants (SVs) and short tandem repeats (STRs), were analysed. An Alzheimer's disease (AD)-related polygenic risk score (PRS) was calculated in patients with AD. RESULTS: Clinical genetic diagnosis was achieved in 7 of 50 (14%) of the patients, with a further 8 patients (16%) found to have established risk factors which may have contributed to their EOD. Two pathogenic variants were identified through SV analysis. No expanded STRs were found in this study cohort, but a blinded analysis with a positive control identified a C9orf72 expansion accurately. Approximately 37% (7 of 19) of patients with AD had a PRS equivalent to >90th percentile risk. DISCUSSION: WGS acts as a single genetic test to identify different types of clinically relevant genetic variations in patients with EOD. WGS, if used as a first-line clinical diagnostic test, has the potential to increase the diagnostic yield and reduce time to diagnosis for EOD.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	BMJ
dc.relation.ispartof	J Neurol Neurosurg Psychiatry
dc.relation.isbasedon	10.1136/jnnp-2021-328146
dc.rights	info:eu-repo/semantics/restrictedAccess
dc.subject	11 Medical and Health Sciences, 17 Psychology and Cognitive Sciences
dc.subject.classification	Neurology & Neurosurgery
dc.title	Clinical impact of whole-genome sequencing in patients with early-onset dementia.
dc.type	Journal Article
utslib.citation.volume	93
utslib.location.activity	England
utslib.for	11 Medical and Health Sciences
utslib.for	17 Psychology and Cognitive Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/Graduate School of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/Graduate School of Health/GSH.Genetic Counselling
utslib.copyright.status	in_progress	*
dc.date.updated	2023-04-04T01:05:44Z
pubs.issue	11
pubs.publication-status	Published online
pubs.volume	93
utslib.citation.issue	11

Abstract:

BACKGROUND: In the clinical setting, identification of the genetic cause in patients with early-onset dementia (EOD) is challenging due to multiple types of genetic tests required to arrive at a diagnosis. Whole-genome sequencing (WGS) has the potential to serve as a single diagnostic platform, due to its superior ability to detect common, rare and structural genetic variation. METHODS: WGS analysis was performed in 50 patients with EOD. Point mutations, small insertions/deletions, as well as structural variants (SVs) and short tandem repeats (STRs), were analysed. An Alzheimer's disease (AD)-related polygenic risk score (PRS) was calculated in patients with AD. RESULTS: Clinical genetic diagnosis was achieved in 7 of 50 (14%) of the patients, with a further 8 patients (16%) found to have established risk factors which may have contributed to their EOD. Two pathogenic variants were identified through SV analysis. No expanded STRs were found in this study cohort, but a blinded analysis with a positive control identified a C9orf72 expansion accurately. Approximately 37% (7 of 19) of patients with AD had a PRS equivalent to >90th percentile risk. DISCUSSION: WGS acts as a single genetic test to identify different types of clinically relevant genetic variations in patients with EOD. WGS, if used as a first-line clinical diagnostic test, has the potential to increase the diagnostic yield and reduce time to diagnosis for EOD.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/169094