title: Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population.
abstract: Hexanucleotide repeat expansions in C9orf72 are a major cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Understanding the disease mechanisms and a method for clinical diagnostic genotyping have been hindered because of the difficulty in estimating the expansion size. We found 96 repeat-primed PCR expansions: 85/2,974 in six neurodegenerative diseases cohorts (FTLD, ALS, Alzheimer disease, sporadic Creutzfeldt-Jakob disease, Huntington disease-like syndrome, and other nonspecific neurodegenerative disease syndromes) and 11/7,579 (0.15%) in UK 1958 birth cohort (58BC) controls. With the use of a modified Southern blot method, the estimated expansion range (smear maxima) in cases was 800-4,400. Similarly, large expansions were detected in the population controls. Differences in expansion size and morphology were detected between DNA samples from tissue and cell lines. Of those in whom repeat-primed PCR detected expansions, 68/69 were confirmed by blotting, which was specific for greater than 275 repeats. We found that morphology in the expansion smear varied among different individuals and among different brain regions in the same individual. Expansion size correlated with age at clinical onset but did not differ between diagnostic groups. Evidence of instability of repeat size in control families, as well as neighboring SNP and microsatellite analyses, support multiple expansion events on the same haplotype background. Our method of estimating the size of large expansions has potential clinical utility. C9orf72-related disease might mimic several neurodegenerative disorders and, with potentially 90,000 carriers in the United Kingdom, is more common than previously realized.
authors: Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, Queen Square, London, UK.
authors: Jon
authors: J
authors: Beck
authors: Mark
authors: M
authors: Poulter
authors: Davina
authors: D
authors: Hensman
authors: Jonathan D
authors: JD
authors: Rohrer
authors: Colin J
authors: CJ
authors: Mahoney
authors: Gary
authors: G
authors: Adamson
authors: Tracy
authors: T
authors: Campbell
authors: James
authors: J
authors: Uphill
authors: Aaron
authors: A
authors: Borg
authors: Pietro
authors: P
authors: Fratta
authors: Richard W
authors: RW
authors: Orrell
authors: Andrea
authors: A
authors: Malaspina
authors: James
authors: J
authors: Rowe
authors: Jeremy
authors: J
authors: Brown
authors: John
authors: J
authors: Hodges
authors: Katie
authors: K
authors: Sidle
authors: James M
authors: JM
authors: Polke
authors: Henry
authors: H
authors: Houlden
authors: Jonathan M
authors: JM
authors: Schott
authors: Nick C
authors: NC
authors: Fox
authors: Martin N
authors: MN
authors: Rossor
authors: Sarah J
authors: SJ
authors: Tabrizi
authors: Adrian M
authors: AM
authors: Isaacs
authors: John
authors: J
authors: Hardy
authors: Jason D
authors: JD
authors: Warren
authors: John
authors: J
authors: Collinge
authors: Simon
authors: S
authors: Mead
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000473:pathology; D000073885:C9orf72 Protein; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D042622:DNA Repeat Expansion; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D018895:Microsatellite Repeats; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D006113:United Kingdom
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins; D004247:DNA