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.
- motor neurone disease
- molecular genetics
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EPM, LH and JAF are joint first authors.
KLW and IPB are joint senior authors.
Twitter @emily__mccann, @Dr_KLWilliams
Contributors Study concept and design: EPM, JAF, KLW with input from LH and IPB. Acquisition of data: major contribution from EPM, LH, JAF and contributions from KYZ, NG, DCB and SCMF. Analysis (including statistical) and interpretation of the data: EPM, LH, JAF and KLW. Data processing: NAT. Collection of clinical information and samples: RP, MCK and DBR. Study supervision: KLW and IPB. Manuscript preparation: EPM and LH. Critical revision of the manuscript: EPM, LH, JAF, KLW and IPB. All authors read and approved the final manuscript.
Funding This work was funded by the Motor Neuron Disease Research Institute of Australia (Grant-in-Aid to KLW, Bill Gole Postdoctoral Fellowship to JAF and PhD top-up scholarship to EPM), National Health and Medical Research Council of Australia (grants 1095215, 1107644 to IPB and fellowship 1092023 to KLW) and Macquarie University (grant to KLW). MCK was supported by the National Health and Medical Research Council of Australia Programme Grant (1132524), Partnership Project (1153439) and Practitioner Fellowship (1156093).
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. The datasets generated and/or analysed during the current study are not publicly available as our ethics permission does not cover sharing of data to third parties, however may be made available on reasonable request to the corresponding author (IPB).
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