title: The genotype-phenotype landscape of familial amyotrophic lateral sclerosis in Australia.
abstract: Amyotrophic lateral sclerosis (ALS) is a clinically and genetically heterogeneous fatal neurodegenerative disease. Around 10% of ALS cases are hereditary. ALS gene discoveries have provided most of our understanding of disease pathogenesis. We aimed to describe the genetic landscape of ALS in Australia by assessing 1013 Australian ALS patients for known ALS mutations by direct sequencing, whole exome sequencing or repeat primed polymerase chain reaction. Age of disease onset and disease duration were used for genotype-phenotype correlations. We report 60.8% of Australian ALS families in this cohort harbour a known ALS mutation. Hexanucleotide repeat expansions in C9orf72 accounted for 40.6% of families and 2.9% of sporadic patients. We also report ALS families with mutations in SOD1 (13.7%), FUS (2.4%), TARDBP (1.9%), UBQLN2 (.9%), OPTN (.5%), TBK1 (.5%) and CCNF (.5%). We present genotype-phenotype correlations between these genes as well as between gene mutations. Notably, C9orf72 hexanucleotide repeat expansion positive patients experienced significantly later disease onset than ALS mutation patients. Among SOD1 families, p.I114T positive patients had significantly later onset and longer survival. Our report highlights a unique spectrum of ALS gene frequencies among patients from the Australian population, and further, provides correlations between specific ALS mutations with disease onset and/or duration.
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Biomedical Sciences, Macquarie University, Sydney, Australia.
authors.forename: E P
authors.identifier: http://orcid.org/0000-0002-8200-3525
authors.initials: EP
authors.lastname: McCann
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Biomedical Sciences, Macquarie University, Sydney, Australia.
authors.forename: K L
authors.initials: KL
authors.lastname: Williams
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Biomedical Sciences, Macquarie University, Sydney, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Fifita
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Biomedical Sciences, Macquarie University, Sydney, Australia.
authors.forename: I S
authors.initials: IS
authors.lastname: Tarr
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, Australia.
authors.forename: J
authors.initials: J
authors.lastname: O'Connor
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Biomedical Sciences, Macquarie University, Sydney, Australia.
authors.forename: D B
authors.initials: DB
authors.lastname: Rowe
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Biomedical Sciences, Macquarie University, Sydney, Australia.|Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, Australia.|Sydney Medical School, University of Sydney, Sydney, Australia.|Molecular Medicine Laboratory, Concord Hospital, Concord, Australia.
authors.forename: G A
authors.initials: GA
authors.lastname: Nicholson
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Biomedical Sciences, Macquarie University, Sydney, Australia.
authors.forename: I P
authors.initials: IP
authors.lastname: Blair
mesh_terms: D017668:Age of Onset; D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D001315:Australia; D000073885:C9orf72 Protein / Q000235:genetics; D005091:Exons; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies / Q000379:methods; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019683:Penetrance; D010641:Phenotype; D017422:Sequence Analysis, DNA; D000072105:Superoxide Dismutase-1 / Q000235:genetics; D000073359:Exome Sequencing
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D000072105:Superoxide Dismutase-1
keywords: amyotrophic lateral sclerosis; correlation; genotype; mutation; phenotype