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Neurobiol Aging. 2014 Oct;35(10):2422.e13-6. doi: 10.1016/j.neurobiolaging.2014.04.026. Epub 2014 May 2.

Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease.

Author information

1
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.
2
University College London (UCL) Institute of Neurology, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
3
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
4
Institute of Psychiatry, King's College London, London, UK.
5
School of Molecular Medical Sciences, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
6
Institute of Brain, Behaviour, and Mental Health, The University of Manchester, Manchester, UK.
7
Cerebral Function Unit Greater Manchester Neuroscience Centre, Manchester, UK.
8
University College London (UCL) Institute of Neurology, London, UK.

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).

KEYWORDS:

APP; British cohort; Early-onset Alzheimer's disease; PSEN1; PSEN2

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