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

卷:420

Article

Eratne, Dhamidhu^1,2,3  Schneider, Amy⁴  Lynch, Ella^3,5  Martyn, Melissa^3,6  Velakoulis, Dennis^1,2  Fahey, Michael^8,9  Kwan, Patrick^10,11,12  Leventer, Richard^6,7,13  Rafehi, Haloom^14,15  Chong, Belinda^5,6,7  Stark, Zornitza^5,6,7  Lunke, Sebastian^5,6,7  Phelan, Dean G.^5,7  O'Keefe, Melanie¹⁶  Siemering, Kirby¹⁶  West, Kirsty^4,8  Sexton, Adrienne⁸  Jarmolowicz, Anna^3,5  Taylor, Jessica A.⁸  Schultz, Joshua⁸  Purvis, Rebecca⁸  Uebergang, Eloise⁷  Chalinor, Heather¹⁷  Creighton, Belinda¹⁷  Gelfand, Nikki¹⁸  Saks, Tamar⁹  Prawer, Yael¹⁸  Smagarinsky, Yana⁶  Pan, Tianxin¹⁹  Goranitis, Ilias^5,19,20  Ademi, Zanfina²¹  Gaff, Clara⁴  Huq, Aamira¹⁷  Walsh, Maie⁸  James, Paul A.^2,3  Krzesinski, Emma I.^9,13  Wallis, Mathew²²  Stutterd, Chloe A.^7,13  Bahlo, Melanie^14,15  Delatycki, Martin B.^6,17  Berkovic, Samuel F.⁵ 

[1] Royal Melbourne Hosp, Neuropsychiat, 300 Grattan St, Melbourne, Vic 3050, Australia

[2] Univ Melbourne, Melbourne Neuropsychiat Ctr, Melbourne, Vic, Australia

[3] Univ Melbourne, Dept Psychiat, Melbourne, Vic, Australia

[4] Melbourne Genom Hlth Alliance, Melbourne, Vic, Australia

[5] Univ Melbourne, Epilepsy Res Ctr, Dept Med, Austin Hlth, Melbourne, Vic, Australia

[6] Victorian Clin Genet Serv, Melbourne, Vic, Australia

[7] Murdoch Childrens Res Inst, Melbourne, Vic, Australia

[8] Royal Melbourne Hosp, Genom Med, Melbourne, Vic, Australia

[9] Monash Hlth, Monash Genet, Melbourne, Vic, Australia

[10] Monash Univ, Alfred Hosp, Cent Clin Sch, Dept Neurosci, Melbourne, Vic, Australia

[11] Univ Melbourne, Royal Melbourne Hosp, Dept Med, Melbourne, Vic, Australia

[12] Univ Melbourne, Royal Melbourne Hosp, Dept Neurol, Melbourne, Vic, Australia

[13] Univ Melbourne, Dept Paediat, Melbourne, Vic, Australia

[14] Walter & Eliza Hall Inst Med Res, Populat Hlth & Immun Div, Melbourne, Vic, Australia

[15] Univ Melbourne, Dept Med Biol, Melbourne, Vic, Australia

[16] Australian Genome Res Facil, Melbourne, Vic, Australia

[17] Clin Genet, Austin Hlth, Melbourne, Vic, Australia

[18] Monash Univ, Dept Paediat, Melbourne, Vic, Australia

[19] Univ Melbourne, Ctr Hlth Policy, Melbourne Sch Populat & Global Hlth, Hlth Econ Unit, Melbourne, Vic, Australia

[20] Australian Genom Hlth Alliance, Melbourne, Vic, Australia

[21] Monash Univ, Sch Publ Hlth & Prevent Med, Melbourne, Vic, Australia

[22] Univ Tasmania, Sch Med, Melbourne, Vic, Australia

关键词: Next generation sequencing;    Neurogenetics;    Neurology;    Neurodegenerative;    Diagnosis;   

DOI  :  10.1016/j.jns.2020.117260

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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