title: Small deletion in C9orf72 hides a proportion of expansion carriers in FTLD.
abstract: Frontotemporal lobar degeneration is a highly familial disease and the most common known genetic cause is the repeat expansion mutation in the gene C9orf72. We have identified 2 brothers with an expansion mutation in C9orf72 using Southern blotting that is undetectable using repeat-primed polymerase chain reaction. Sequencing using high concentrations of DNA denaturants of a bacterial artificial chromosome clone obtained from one of the brothers identified a 10-base pair deletion adjacent to the expansion that presumably confers strong secondary structure that interferes with the genotyping. Using an alternative method, we have identified missed expansion carriers in our cohort, and this number has increased by approximately 25%. This observation has important implications for patients undergoing genetic testing for C9orf72.
authors.affiliation: Faculty of Human and Medical Sciences, Institute of Brain Behaviour and Mental Health, University of Manchester, Manchester, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Rollinson
authors.affiliation: Faculty of Human and Medical Sciences, Institute of Brain Behaviour and Mental Health, University of Manchester, Manchester, UK.
authors.forename: Janis
authors.initials: J
authors.lastname: Bennion Callister
authors.affiliation: Faculty of Human and Medical Sciences, Institute of Brain Behaviour and Mental Health, University of Manchester, Manchester, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Young
authors.affiliation: Faculty of Human and Medical Sciences, Institute of Brain Behaviour and Mental Health, University of Manchester, Manchester, UK.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Ryan
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
authors.forename: Ronald
authors.initials: R
authors.lastname: Druyeh
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Rohrer
authors.affiliation: Mental Health and Neurodegeneration Research Group, Faculty of Human and Medical Sciences, University of Manchester, Salford Royal Hospital, Salford, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Snowden
authors.affiliation: Mental Health and Neurodegeneration Research Group, Faculty of Human and Medical Sciences, University of Manchester, Salford Royal Hospital, Salford, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Richardson
authors.affiliation: Mental Health and Neurodegeneration Research Group, Faculty of Human and Medical Sciences, University of Manchester, Salford Royal Hospital, Salford, UK.
authors.forename: Matt
authors.initials: M
authors.lastname: Jones
authors.affiliation: Mental Health and Neurodegeneration Research Group, Faculty of Human and Medical Sciences, University of Manchester, Salford Royal Hospital, Salford, UK.
authors.forename: Jenny
authors.initials: J
authors.lastname: Harris
authors.affiliation: Mental Health and Neurodegeneration Research Group, Faculty of Human and Medical Sciences, University of Manchester, Salford Royal Hospital, Salford, UK.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Davidson
authors.affiliation: Mental Health and Neurodegeneration Research Group, Faculty of Human and Medical Sciences, University of Manchester, Salford Royal Hospital, Salford, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Robinson
authors.affiliation: MND Care Centre, Greater Manchester Neurosciences Centre, Salford Royal NHS Foundation Trust.
authors.forename: John
authors.initials: J
authors.lastname: Ealing
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Janel O
authors.initials: JO
authors.lastname: Johnson
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Traynor
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
authors.affiliation: Mental Health and Neurodegeneration Research Group, Faculty of Human and Medical Sciences, University of Manchester, Salford Royal Hospital, Salford, UK.
authors.forename: David
authors.initials: D
authors.lastname: Mann
authors.affiliation: Faculty of Human and Medical Sciences, Institute of Brain Behaviour and Mental Health, University of Manchester, Manchester, UK. Electronic address: SPB@Manchester.ac.uk.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Pickering-Brown
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000073885:C9orf72 Protein; D015331:Cohort Studies; D042622:DNA Repeat Expansion / Q000235:genetics*; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000453:epidemiology / Q000235:genetics*; D017353:Gene Deletion; D005820:Genetic Testing / Q000379:methods; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D055815:Young Adult
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins
keywords: ALS; C9orf72; FTLD; Frontotemporal lobar degeneration; Repeat expansion