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

Autor:	Eratne D; Neuropsychiatry, Royal Melbourne Hospital, Melbourne, Australia; Melbourne Neuropsychiatry Centre & Department of Psychiatry, University of Melbourne, Melbourne, Australia; Melbourne Genomics Health Alliance, Melbourne, Australia. Electronic address: dhamidhu.eratne@mh.org.au., Schneider A; Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC, Australia., Lynch E; Melbourne Genomics Health Alliance, Melbourne, Australia; Victorian Clinical Genetics Services, Melbourne, Australia., Martyn M; Melbourne Genomics Health Alliance, Melbourne, Australia; Murdoch Children's Research Institute, Melbourne, Australia., Velakoulis D; Neuropsychiatry, Royal Melbourne Hospital, Melbourne, Australia; Melbourne Neuropsychiatry Centre & Department of Psychiatry, University of Melbourne, Melbourne, Australia., Fahey M; Genomic Medicine, Royal Melbourne Hospital, Melbourne, Australia; Monash Genetics, Monash Health, Melbourne, Australia., Kwan P; Department of Neuroscience, Central Clinical School, Monash University, Alfred Hospital, Melbourne, Australia; Departments of Medicine and Neurology, The University of Melbourne, Royal Melbourne Hospital, Melbourne, Australia., Leventer R; Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia., Rafehi H; Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Chong B; Victorian Clinical Genetics Services, Melbourne, Australia; Murdoch Children's Research Institute, Melbourne, Australia., Stark Z; Victorian Clinical Genetics Services, Melbourne, Australia; Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia., Lunke S; Victorian Clinical Genetics Services, Melbourne, Australia; Murdoch Children's Research Institute, Melbourne, Australia., Phelan DG; Victorian Clinical Genetics Services, Melbourne, Australia; Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia., O'Keefe M; Australian Genome Research Facility, Melbourne, Australia., Siemering K; Australian Genome Research Facility, Melbourne, Australia., West K; Melbourne Genomics Health Alliance, Melbourne, Australia; Genomic Medicine, Royal Melbourne Hospital, Melbourne, Australia., Sexton A; Genomic Medicine, Royal Melbourne Hospital, Melbourne, Australia., Jarmolowicz A; Melbourne Genomics Health Alliance, Melbourne, Australia; Victorian Clinical Genetics Services, Melbourne, Australia; Genomic Medicine, Royal Melbourne Hospital, Melbourne, Australia., Taylor JA; Genomic Medicine, Royal Melbourne Hospital, Melbourne, Australia., Schultz J; Genomic Medicine, Royal Melbourne Hospital, Melbourne, Australia., Purvis R; Genomic Medicine, Royal Melbourne Hospital, Melbourne, Australia., Uebergang E; Murdoch Children's Research Institute, Melbourne, Australia., Chalinor H; Clinical Genetics, Austin Health, Melbourne, Australia., Creighton B; Melbourne Genomics Health Alliance, Melbourne, Australia; Clinical Genetics, Austin Health, Melbourne, Australia., Gelfand N; Monash Genetics, Monash Health, Melbourne, Australia; Department of Paediatrics, Monash University, Melbourne, Australia., Saks T; Monash Genetics, Monash Health, Melbourne, Australia., Prawer Y; Monash Genetics, Monash Health, Melbourne, Australia; Department of Paediatrics, Monash University, Melbourne, Australia., Smagarinsky Y; Victorian Clinical Genetics Services, Melbourne, Australia., Pan T; Health Economics Unit, Centre for Health Policy, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia., Goranitis I; Health Economics Unit, Centre for Health Policy, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia; Australian Genomics Health Alliance, Melbourne, Australia., Ademi Z; School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia., Gaff C; Melbourne Genomics Health Alliance, Melbourne, Australia., Huq A; Clinical Genetics, Austin Health, Melbourne, Australia., Walsh M; Genomic Medicine, Royal Melbourne Hospital, Melbourne, Australia., James PA; Genomic Medicine, Royal Melbourne Hospital, Melbourne, Australia., Krzesinski EI; Monash Genetics, Monash Health, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia., Wallis M; Clinical Genetics, Austin Health, Melbourne, Australia; School of Medicine, University of Tasmania, Australia., Stutterd CA; Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia; Clinical Genetics, Austin Health, Melbourne, Australia., Bahlo M; Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Delatycki MB; Victorian Clinical Genetics Services, Melbourne, Australia; Clinical Genetics, Austin Health, Melbourne, Australia., Berkovic SF; Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC, Australia.
Jazyk:	angličtina
Zdroj:	Journal of the neurological sciences [J Neurol Sci] 2021 Jan 15; Vol. 420, pp. 117260. Date of Electronic Publication: 2020 Dec 03.
DOI:	10.1016/j.jns.2020.117260
Abstrakt:	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. (Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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