The clinical utility of exome sequencing and extended bioinformatic analyses in adolescents and adults with a broad range of neurological phenotypes: an Australian perspective.

Eratne, D; Schneider, A; Lynch, E; Martyn, M; Velakoulis, D; Fahey, M; Kwan, P; Leventer, R; Rafehi, H; Chong, B; Stark, Z; Lunke, S; Phelan, DG; O'Keefe, M; Siemering, K; West, K; Sexton, A; Jarmolowicz, A; Taylor, JA; Schultz, J; Purvis, R; Uebergang, E; Chalinor, H; Creighton, B; Gelfand, N; Saks, T; Prawer, Y; Smagarinsky, Y; Pan, T; Goranitis, I; Ademi, Z; Gaff, C; Huq, A; Walsh, M; James, PA; Krzesinski, EI; Wallis, M; Stutterd, CA; Bahlo, M; Delatycki, MB; Berkovic, SF

The clinical utility of exome sequencing and extended bioinformatic analyses in adolescents and adults with a broad range of neurological phenotypes: an Australian perspective.

Eratne, D Schneider, A Lynch, E Martyn, M Velakoulis, D Fahey, M Kwan, P Leventer, R Rafehi, H Chong, B Stark, Z Lunke, S Phelan, DG O'Keefe, M Siemering, K West, K Sexton, A

Jarmolowicz, A Taylor, JA Schultz, J Purvis, R Uebergang, E Chalinor, H Creighton, B Gelfand, N Saks, T Prawer, Y Smagarinsky, Y Pan, T Goranitis, I Ademi, Z Gaff, C Huq, A Walsh, M James, PA Krzesinski, EI Wallis, M Stutterd, CA Bahlo, M Delatycki, MB Berkovic, SF

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Publisher:: Ege University Press
Publication Type:: Journal Article
Citation:: Journal of Neurological Sciences, 2021, 420, pp. 1-8
Issue Date:: 2021-01-15

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Field	Value	Language
dc.contributor.author	Eratne, D
dc.contributor.author	Schneider, A
dc.contributor.author	Lynch, E
dc.contributor.author	Martyn, M
dc.contributor.author	Velakoulis, D
dc.contributor.author	Fahey, M
dc.contributor.author	Kwan, P
dc.contributor.author	Leventer, R
dc.contributor.author	Rafehi, H
dc.contributor.author	Chong, B
dc.contributor.author	Stark, Z
dc.contributor.author	Lunke, S
dc.contributor.author	Phelan, DG
dc.contributor.author	O'Keefe, M
dc.contributor.author	Siemering, K
dc.contributor.author	West, K
dc.contributor.author	Sexton, A https://orcid.org/0000-0001-8749-1639
dc.contributor.author	Jarmolowicz, A
dc.contributor.author	Taylor, JA
dc.contributor.author	Schultz, J
dc.contributor.author	Purvis, R
dc.contributor.author	Uebergang, E
dc.contributor.author	Chalinor, H
dc.contributor.author	Creighton, B
dc.contributor.author	Gelfand, N
dc.contributor.author	Saks, T
dc.contributor.author	Prawer, Y
dc.contributor.author	Smagarinsky, Y
dc.contributor.author	Pan, T
dc.contributor.author	Goranitis, I
dc.contributor.author	Ademi, Z
dc.contributor.author	Gaff, C
dc.contributor.author	Huq, A
dc.contributor.author	Walsh, M
dc.contributor.author	James, PA
dc.contributor.author	Krzesinski, EI
dc.contributor.author	Wallis, M
dc.contributor.author	Stutterd, CA
dc.contributor.author	Bahlo, M
dc.contributor.author	Delatycki, MB
dc.contributor.author	Berkovic, SF
dc.date.accessioned	2022-02-17T22:02:49Z
dc.date.available	2020-11-30
dc.date.available	2022-02-17T22:02:49Z
dc.date.issued	2021-01-15
dc.identifier.citation	Journal of Neurological Sciences, 2021, 420, pp. 1-8
dc.identifier.issn	1300-1817
dc.identifier.issn	1878-5883
dc.identifier.uri	http://hdl.handle.net/10453/154663
dc.description.abstract	Currently there is no secured ongoing funding in Australia for next generation sequencing (NGS) such as exome sequencing (ES) for adult neurological disorders. Studies have focused on paediatric populations in research or highly specialised settings, utilised standard NGS pipelines focusing only on small insertions, deletions and single nucleotide variants, and not explored impacts on management in detail. This prospective multi-site study performed ES and an extended bioinformatics repeat expansion analysis pipeline, on patients with broad phenotypes (ataxia, dementia, dystonia, spastic paraparesis, motor neuron disease, Parkinson's disease and complex/not-otherwise-specified), with symptom onset between 2 and 60 years. Genomic data analysis was phenotype-driven, using virtual gene panels, reported according to American College of Medical Genetics and Genomics guidelines. One-hundred-and-sixty patients (51% female) were included, median age 52 years (range 14-79) and median 9 years of symptoms. 34/160 (21%) patients received a genetic diagnosis. Highest diagnostic rates were in spastic paraparesis (10/25, 40%), complex/not-otherwise-specified (10/38, 26%) and ataxia (7/28, 25%) groups. Findings were considered 'possible/uncertain' in 21/160 patients. Repeat expansion detection identified an unexpected diagnosis of Huntington disease in an ataxic patient with negative ES. Impacts on management, such as more precise and tailored care, were seen in most diagnosed patients (23/34, 68%). ES and a novel bioinformatics analysis pipepline had a substantial diagnostic yield (21%) and management impacts for most diagnosed patients, in heterogeneous, complex, mainly adult-onset neurological disorders in real-world settings in Australia, providing evidence for NGS and complementary multiple, new technologies as valuable diagnostic tools.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Ege University Press
dc.relation.ispartof	Journal of Neurological Sciences
dc.relation.isbasedon	10.1016/j.jns.2020.117260
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1103 Clinical Sciences, 1109 Neurosciences
dc.subject.classification	Neurology & Neurosurgery
dc.subject.mesh	Adolescent
dc.subject.mesh	Adult
dc.subject.mesh	Aged
dc.subject.mesh	Australia
dc.subject.mesh	Child
dc.subject.mesh	Computational Biology
dc.subject.mesh	Exome
dc.subject.mesh	Female
dc.subject.mesh	Genetic Testing
dc.subject.mesh	High-Throughput Nucleotide Sequencing
dc.subject.mesh	Humans
dc.subject.mesh	Male
dc.subject.mesh	Middle Aged
dc.subject.mesh	Phenotype
dc.subject.mesh	Prospective Studies
dc.subject.mesh	Young Adult
dc.subject.mesh	Adolescent
dc.subject.mesh	Adult
dc.subject.mesh	Aged
dc.subject.mesh	Australia
dc.subject.mesh	Child
dc.subject.mesh	Computational Biology
dc.subject.mesh	Exome
dc.subject.mesh	Female
dc.subject.mesh	Genetic Testing
dc.subject.mesh	High-Throughput Nucleotide Sequencing
dc.subject.mesh	Humans
dc.subject.mesh	Male
dc.subject.mesh	Middle Aged
dc.subject.mesh	Phenotype
dc.subject.mesh	Prospective Studies
dc.subject.mesh	Young Adult
dc.subject.mesh	Humans
dc.subject.mesh	Prospective Studies
dc.subject.mesh	Computational Biology
dc.subject.mesh	Phenotype
dc.subject.mesh	Adolescent
dc.subject.mesh	Adult
dc.subject.mesh	Aged
dc.subject.mesh	Middle Aged
dc.subject.mesh	Child
dc.subject.mesh	Australia
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Young Adult
dc.subject.mesh	Genetic Testing
dc.subject.mesh	High-Throughput Nucleotide Sequencing
dc.subject.mesh	Exome
dc.title	The clinical utility of exome sequencing and extended bioinformatic analyses in adolescents and adults with a broad range of neurological phenotypes: an Australian perspective.
dc.type	Journal Article
utslib.citation.volume	420
utslib.location.activity	Netherlands
utslib.for	1103 Clinical Sciences
utslib.for	1109 Neurosciences
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	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2022-02-17T22:02:47Z
pubs.publication-status	Published
pubs.volume	420

Abstract:

Currently there is no secured ongoing funding in Australia for next generation sequencing (NGS) such as exome sequencing (ES) for adult neurological disorders. Studies have focused on paediatric populations in research or highly specialised settings, utilised standard NGS pipelines focusing only on small insertions, deletions and single nucleotide variants, and not explored impacts on management in detail. This prospective multi-site study performed ES and an extended bioinformatics repeat expansion analysis pipeline, on patients with broad phenotypes (ataxia, dementia, dystonia, spastic paraparesis, motor neuron disease, Parkinson's disease and complex/not-otherwise-specified), with symptom onset between 2 and 60 years. Genomic data analysis was phenotype-driven, using virtual gene panels, reported according to American College of Medical Genetics and Genomics guidelines. One-hundred-and-sixty patients (51% female) were included, median age 52 years (range 14-79) and median 9 years of symptoms. 34/160 (21%) patients received a genetic diagnosis. Highest diagnostic rates were in spastic paraparesis (10/25, 40%), complex/not-otherwise-specified (10/38, 26%) and ataxia (7/28, 25%) groups. Findings were considered 'possible/uncertain' in 21/160 patients. Repeat expansion detection identified an unexpected diagnosis of Huntington disease in an ataxic patient with negative ES. Impacts on management, such as more precise and tailored care, were seen in most diagnosed patients (23/34, 68%). ES and a novel bioinformatics analysis pipepline had a substantial diagnostic yield (21%) and management impacts for most diagnosed patients, in heterogeneous, complex, mainly adult-onset neurological disorders in real-world settings in Australia, providing evidence for NGS and complementary multiple, new technologies as valuable diagnostic tools.

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

http://hdl.handle.net/10453/154663