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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 and Schneider, A and Lynch, E and Martyn, M and Velakoulis, D and Fahey, M and Kwan, P and Leventer, R and Rafehi, H and Chong, B and Stark, Z and Lunke, S and Phelan, DG and O'Keefe, M and Siemering, K and West, K and Sexton, A and Jarmolowicz, A and Taylor, JA and Schultz, J and Purvis, R and Uebergang, E and Chalinor, H and Creighton, B and Gelfand, N and Saks, T and Prawer, Y and Smagarinsky, Y and Pan, T and Goranitis, I and Ademi, Z and Gaff, C and Huq, A and Walsh, M and James, PA and Krzesinski, EI and Wallis, M and Stutterd, CA and Bahlo, M and Delatycki, MB and 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, Journal of the Neurological Sciences, 420 ISSN 0022-510X (2021) [Refereed Article]

Copyright Statement

© 2020 Elsevier B.V. All rights reserved.

DOI: doi:10.1016/j.jns.2020.117260


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 14â€"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.

Item Details

Item Type:Refereed Article
Keywords:diagnosis, neurodegenerative, neurogenetics, neurology, next generation sequencing
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Neurology and neuromuscular diseases
Objective Division:Health
Objective Group:Clinical health
Objective Field:Diagnosis of human diseases and conditions
UTAS Author:Wallis, M (Dr Mathew Wallis)
ID Code:145720
Year Published:2021
Web of Science® Times Cited:5
Deposited By:UTAS Centre for Rural Health
Deposited On:2021-08-03
Last Modified:2022-08-23

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