Evidence for polygenic and oligogenic basis of Australian sporadic amyotrophic lateral sclerosis.

Autor:	McCann EP; Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia., Henden L; Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia., Fifita JA; Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia., Zhang KY; Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia., Grima N; Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia., Bauer DC; Transformational Bioinformatics, Commonwealth Scientific and Industrial Research Organisation, Sydney, New South Wales, Australia., Chan Moi Fat S; Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia., Twine NA; Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.; Transformational Bioinformatics, Commonwealth Scientific and Industrial Research Organisation, Sydney, New South Wales, Australia., Pamphlett R; Discipline of Pathology and Department of Neuropathology, The University of Sydney, Sydney, New South Wales, Australia.; Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia.; Department of Neuropathology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia., Kiernan MC; Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia.; Institute of Clinical Neurosciences, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia., Rowe DB; Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.; Department of Clinical Medicine, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia., Williams KL; Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia., Blair IP; Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia ian.blair@mq.edu.au.
Jazyk:	angličtina
Zdroj:	Journal of medical genetics [J Med Genet] 2020 May 14. Date of Electronic Publication: 2020 May 14.
DOI:	10.1136/jmedgenet-2020-106866
Abstrakt:	Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with phenotypic and genetic heterogeneity. Approximately 10% of cases are familial, while remaining cases are classified as sporadic. To date, >30 genes and several hundred genetic variants have been implicated in ALS. Methods: Seven hundred and fifty-seven sporadic ALS cases were recruited from Australian neurology clinics. Detailed clinical data and whole genome sequencing (WGS) data were available from 567 and 616 cases, respectively, of which 426 cases had both datasets available. As part of a comprehensive genetic analysis, 853 genetic variants previously reported as ALS-linked mutations or disease-associated alleles were interrogated in sporadic ALS WGS data. Statistical analyses were performed to identify correlation between clinical variables, and between phenotype and the number of ALS-implicated variants carried by an individual. Relatedness between individuals carrying identical variants was assessed using identity-by-descent analysis. Results: Forty-three ALS-implicated variants from 18 genes, including C9orf72 , ATXN2 , TARDBP, SOD1, SQSTM1 and SETX, were identified in Australian sporadic ALS cases. One-third of cases carried at least one variant and 6.82% carried two or more variants, implicating a potential oligogenic or polygenic basis of ALS. Relatedness was detected between two sporadic ALS cases carrying a SOD1 p.I114T mutation, and among three cases carrying a SQSTM1 p.K238E mutation. Oligogenic/polygenic sporadic ALS cases showed earlier age of onset than those with no reported variant. Conclusion: We confirm phenotypic associations among ALS cases, and highlight the contribution of genetic variation to all forms of ALS. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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