title: Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease.
abstract: Early-onset Alzheimer's disease (EOAD) represents 1%-2% of the Alzheimer's disease (AD) cases, and it is generally characterized by a positive family history and a rapidly progressive symptomatology. Rare coding and fully penetrant variants in amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the only causative mutations reported for autosomal dominant AD. Thus, in this study we used exome sequencing data to rapidly screen rare coding variability in APP, PSEN1, and PSEN2, in a British cohort composed of 47 unrelated EOAD cases and 179 elderly controls, neuropathologically proven. We report 2 novel and likely pathogenic variants in PSEN1 (p.L166V and p.S230R). A comprehensive catalog of rare pathogenic variants in the AD Mendelian genes is pivotal for a premortem diagnosis of autosomal dominant EOAD and for the differential diagnosis with other early onset dementias such as frontotemporal dementia (FTD) and Creutzfeldt-Jakob disease (CJD).
authors.affiliation: University College London (UCL) Institute of Neurology, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. Electronic address: celeste.sassi.10@ucl.ac.uk.
authors.forename: Celeste
authors.initials: C
authors.lastname: Sassi
authors.affiliation: University College London (UCL) Institute of Neurology, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Guerreiro
authors.affiliation: University College London (UCL) Institute of Neurology, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Gibbs
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Ding
authors.affiliation: Institute of Psychiatry, King's College London, London, UK.
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Lupton
authors.affiliation: Institute of Psychiatry, King's College London, London, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.affiliation: Institute of Psychiatry, King's College London, London, UK.
authors.forename: Katie
authors.initials: K
authors.lastname: Lunnon
authors.affiliation: Institute of Psychiatry, King's College London, London, UK.
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
authors.affiliation: School of Molecular Medical Sciences, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
authors.forename: Kristelle S
authors.initials: KS
authors.lastname: Brown
authors.affiliation: School of Molecular Medical Sciences, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
authors.forename: Chirstopher
authors.initials: C
authors.lastname: Medway
authors.affiliation: School of Molecular Medical Sciences, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
authors.forename: Jenny
authors.initials: J
authors.lastname: Lord
authors.affiliation: School of Molecular Medical Sciences, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
authors.forename: James
authors.initials: J
authors.lastname: Turton
authors.affiliation: Institute of Brain, Behaviour, and Mental Health, The University of Manchester, Manchester, UK.
authors.forename: David
authors.initials: D
authors.lastname: Mann
authors.affiliation: Cerebral Function Unit Greater Manchester Neuroscience Centre, Manchester, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Snowden
authors.affiliation: Cerebral Function Unit Greater Manchester Neuroscience Centre, Manchester, UK.
authors.forename: David
authors.initials: D
authors.lastname: Neary
authors.affiliation: Cerebral Function Unit Greater Manchester Neuroscience Centre, Manchester, UK.
authors.forename: Jeniffer
authors.initials: J
authors.lastname: Harris
authors.affiliation: University College London (UCL) Institute of Neurology, London, UK.
authors.forename: Jose
authors.initials: J
authors.lastname: Bras
authors.affiliation: School of Molecular Medical Sciences, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Morgan
authors.affiliation: Institute of Psychiatry, King's College London, London, UK.
authors.forename: John F
authors.initials: JF
authors.lastname: Powell
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.affiliation: University College London (UCL) Institute of Neurology, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D015331:Cohort Studies; D003937:Diagnosis, Differential; D059472:Exome / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D053764:Presenilin-1 / Q000235:genetics*; D053766:Presenilin-2 / Q000235:genetics; D017422:Sequence Analysis, DNA; D006113:United Kingdom
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D053766:Presenilin-2
keywords: APP; British cohort; Early-onset Alzheimer's disease; PSEN1; PSEN2