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

Celeste Sassi, Rita Guerreiro, Raphael Gibbs, Jinhui Ding, Michelle K Lupton, Claire Troakes, Katie Lunnon, Safa Al-Sarraj, Kristelle S Brown, Chirstopher Medway, Jenny Lord, James Turton, David Mann, Julie Snowden, David Neary, Jeniffer Harris, Jose Bras, Kevin Morgan, John F Powell, Andrew SingletonJohn Hardy, ARUK Consortium, Patrick Kehoe

Research output: Contribution to journalArticle (Academic Journal)peer-review

24 Citations (Scopus)


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).

Original languageEnglish
Pages (from-to)2422.e13-6
JournalNeurobiology of Aging
Issue number10
Publication statusPublished - Oct 2014

Bibliographical note

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.


  • Adult
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease
  • Amyloid beta-Protein Precursor
  • Cohort Studies
  • Diagnosis, Differential
  • Exome
  • Female
  • Genes, Dominant
  • Genetic Association Studies
  • Great Britain
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Presenilin-1
  • Presenilin-2
  • Sequence Analysis, DNA


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