Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
24880964
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).
Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
DATE PUBLISHED
2014 Oct
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2014/03/16
accepted 2014/04/22
aheadofprint 2014/05/02
entrez 2014/06/02 06:00
pubmed 2014/06/02 06:00
medline 2015/02/11 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Sassi C Sassi Celeste C 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.
Guerreiro R Guerreiro Rita R University College London (UCL) Institute of Neurology, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Gibbs R Gibbs Raphael R University College London (UCL) Institute of Neurology, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Ding J Ding Jinhui J Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Lupton MK Lupton Michelle K MK Institute of Psychiatry, King's College London, London, UK.
Troakes C Troakes Claire C Institute of Psychiatry, King's College London, London, UK.
Lunnon K Lunnon Katie K Institute of Psychiatry, King's College London, London, UK.
Al-Sarraj S Al-Sarraj Safa S Institute of Psychiatry, King's College London, London, UK.
Brown KS Brown Kristelle S KS School of Molecular Medical Sciences, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
Medway C Medway Chirstopher C School of Molecular Medical Sciences, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
Lord J Lord Jenny J School of Molecular Medical Sciences, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
Turton J Turton James J School of Molecular Medical Sciences, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
Mann D Mann David D Institute of Brain, Behaviour, and Mental Health, The University of Manchester, Manchester, UK.
Snowden J Snowden Julie J Cerebral Function Unit Greater Manchester Neuroscience Centre, Manchester, UK.
Neary D Neary David D Cerebral Function Unit Greater Manchester Neuroscience Centre, Manchester, UK.
Harris J Harris Jeniffer J Cerebral Function Unit Greater Manchester Neuroscience Centre, Manchester, UK.
Bras J Bras Jose J University College London (UCL) Institute of Neurology, London, UK.
ARUK Consortium
Morgan K Morgan Kevin K School of Molecular Medical Sciences, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
Powell JF Powell John F JF Institute of Psychiatry, King's College London, London, UK.
Singleton A Singleton Andrew A Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Hardy J Hardy John J University College London (UCL) Institute of Neurology, London, UK.
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
Passmore Peter P
Craig David D
Johnston Janet J
McGuinness Bernadette B
Todd Stephen S
Heun Reinhard R
Kölsch Heike H
Kehoe Patrick G PG
Hooper Nigel M NM
Vardy Emma R L C ER
Mann David M DM
Pickering-Brown Stuart S
Brown Kristelle K
Lowe James J
Morgan Kevin K
Smith A David A
Wilcock Gordon G
Warden Donald D
Holmes Clive C
JOURNAL
VOLUME: 35
ISSUE: 10
TITLE: Neurobiology of aging
ISOABBREVIATION: Neurobiol. Aging
YEAR: 2014
MONTH: Oct
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1558-1497
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Neurobiol Aging
COUNTRY: United States
ISSNLINKING: 0197-4580
NLMUNIQUEID: 8100437
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
089698 Wellcome Trust United Kingdom
089701 Wellcome Trust United Kingdom
G-1107 Parkinson's UK United Kingdom
G0701441 Medical Research Council United Kingdom
G1100695 Medical Research Council United Kingdom
P50 AG016574 NIA NIH HHS United States
R01 AG18023 NIA NIH HHS United States
U01 AG006786 NIA NIH HHS United States
WT089698 Wellcome Trust United Kingdom
ZO1 AG000950-10 NIA NIH HHS United States
GENERAL NOTE
KEYWORDS
KEYWORD
APP
British cohort
Early-onset Alzheimer's disease
PSEN1
PSEN2
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adult
Aged
Aged, 80 and over
Alzheimer Disease genetics
Amyloid beta-Protein Precursor genetics
Cohort Studies genetics
Diagnosis, Differential genetics
Exome genetics
Female genetics
Genes, Dominant genetics
Genetic Association Studies genetics
Great Britain genetics
Humans genetics
Male genetics
Middle Aged genetics
Mutation genetics
Presenilin-1 genetics
Presenilin-2 genetics
Sequence Analysis, DNA genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Amyloid beta-Protein Precursor
0 Presenilin-1
0 Presenilin-2
OTHER ID's
OTHERID SOURCE
PMC4099516 NLM
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