title: Screening a UK amyotrophic lateral sclerosis cohort provides evidence of multiple origins of the C9orf72 expansion.
abstract: An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Although 0-30 hexanucleotide repeats are present in the general population, expansions >500 repeats are associated with C9ALS/FTD. Large C9ALS/FTD expansions share a common haplotype and whether these expansions derive from a single founder or occur more frequently on a predisposing haplotype is yet to be determined and is relevant to disease pathomechanisms. Furthermore, although cases carrying 50-200 repeats have been described, their role and the pathogenic threshold of the expansions remain to be identified and carry importance for diagnostics and genetic counseling. We present clinical and genetic data from a UK ALS cohort and report the detailed molecular study of an atypical somatically unstable expansion of 90 repeats. Our results across different tissues provide evidence for the pathogenicity of this repeat number by showing they can somatically expand in the central nervous system to the well characterized pathogenic range. Our results support the occurrence of multiple expansion events for C9ALS/FTD.
authors.affiliation: Department of Neurodegenerative Disease, University College London, Queen Square, London, UK; MRC Centre for Neuromuscular Diseases, University College London, Queen Square, London, UK. Electronic address: p.fratta@ucl.ac.uk.
authors.forename: Pietro
authors.initials: P
authors.lastname: Fratta
authors.affiliation: Neurogenetics Unit, Queen Square, London, UK. Electronic address: James.Polke@uclh.nhs.uk.
authors.forename: James M
authors.initials: JM
authors.lastname: Polke
authors.affiliation: NeuroResource, Institute of Neurology, University College London, Queen Square, London, UK.
authors.forename: Jia
authors.initials: J
authors.lastname: Newcombe
authors.affiliation: Department of Neurodegenerative Disease, University College London, Queen Square, London, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Mizielinska
authors.affiliation: Queen Square Brain Bank for Neurological Disorders, University College London, Queen Square, London, UK.
authors.forename: Tammaryn
authors.initials: T
authors.lastname: Lashley
authors.affiliation: Department of Neurodegenerative Disease, University College London, Queen Square, London, UK; MRC Prion Unit, University College London, Queen Square, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Poulter
authors.affiliation: Department of Neurodegenerative Disease, University College London, Queen Square, London, UK; MRC Prion Unit, University College London, Queen Square, London, UK.
authors.forename: Jon
authors.initials: J
authors.lastname: Beck
authors.affiliation: Department of Molecular Neuroscience, University College London, Queen Square, London, UK.
authors.forename: Elisavet
authors.initials: E
authors.lastname: Preza
authors.affiliation: Department of Neurodegenerative Disease, University College London, Queen Square, London, UK.
authors.forename: Anny
authors.initials: A
authors.lastname: Devoy
authors.affiliation: Department of Molecular Neuroscience, University College London, Queen Square, London, UK; National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
authors.forename: Katie
authors.initials: K
authors.lastname: Sidle
authors.affiliation: National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Howard
authors.affiliation: National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; Centre for Neuroscience & Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Malaspina
authors.affiliation: MRC Centre for Neuromuscular Diseases, University College London, Queen Square, London, UK; Department of Molecular Neuroscience, University College London, Queen Square, London, UK; National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Orrell
authors.affiliation: National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
authors.forename: Jan
authors.initials: J
authors.lastname: Clarke
authors.affiliation: Centre for Neuroscience & Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK; Sobell Department of Motor Neuroscience and Movement Disorders, University College London, Queen Square, London, UK.
authors.forename: Ching-Hua
authors.initials: CH
authors.lastname: Lu
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, University College London, Queen Square, London, UK.
authors.forename: Kin
authors.initials: K
authors.lastname: Mok
authors.affiliation: Department of Neurodegenerative Disease, University College London, Queen Square, London, UK.
authors.forename: Toby
authors.initials: T
authors.lastname: Collins
authors.affiliation: Department of Molecular Neuroscience, University College London, Queen Square, London, UK.
authors.forename: Maryam
authors.initials: M
authors.lastname: Shoaii
authors.affiliation: Neurogenetics Unit, Queen Square, London, UK.
authors.forename: Tina
authors.initials: T
authors.lastname: Nanji
authors.affiliation: Department of Molecular Neuroscience, University College London, Queen Square, London, UK.
authors.forename: Selina
authors.initials: S
authors.lastname: Wray
authors.affiliation: Department of Neurodegenerative Disease, University College London, Queen Square, London, UK; MRC Prion Unit, University College London, Queen Square, London, UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Adamson
authors.affiliation: Department of Molecular Neuroscience, University College London, Queen Square, London, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Pittman
authors.affiliation: Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institutes of Health, National Institute on Aging, Bethesda, MD, USA.
authors.forename: Alan E
authors.initials: AE
authors.lastname: Renton
authors.affiliation: Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institutes of Health, National Institute on Aging, Bethesda, MD, USA.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.affiliation: Neurogenetics Unit, Queen Square, London, UK.
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sweeney
authors.affiliation: Queen Square Brain Bank for Neurological Disorders, University College London, Queen Square, London, UK.
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
authors.affiliation: Neurogenetics Unit, Queen Square, London, UK; Department of Molecular Neuroscience, University College London, Queen Square, London, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: Department of Neurodegenerative Disease, University College London, Queen Square, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
authors.affiliation: Department of Neurodegenerative Disease, University College London, Queen Square, London, UK.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Isaacs
authors.affiliation: Department of Neurodegenerative Disease, University College London, Queen Square, London, UK; MRC Centre for Neuromuscular Diseases, University College London, Queen Square, London, UK. Electronic address: e.fisher@prion.ucl.ac.uk.
authors.forename: Elizabeth M C
authors.initials: EM
authors.lastname: Fisher
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000073885:C9orf72 Protein; D015331:Cohort Studies; D042622:DNA Repeat Expansion / Q000235:genetics*; D057180:Frontotemporal Dementia / Q000235:genetics; D006801:Humans; D011506:Proteins / Q000235:genetics*; D006113:United Kingdom
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins
keywords: Amyotrophic lateral sclerosis; Frontotemporal dementia; Somatic instability