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

Celeste Sassi,Rita Guerreiro,Jeniffer Harris,David Neary,Chirstopher Medway,Katie Lunnon,Jenny Lord,Michelle K Lupton,Raphael Gibbs,Jinhui Ding,Kevin Morgan,David Mann,James Turton,John Hardy,Claire Troakes,John Powell ,Safa Al‐Sarraj ,Kristelle Brown ,Julie S Snowden ,José Brás ,Andrew Singleton

doi:10.1016/j.neurobiolaging.2014.04.026

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).

Highlights

We report the experience of a mutation screening in amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) in 47 Early-onset Alzheimer’s disease (EOAD) unrelated cases and 179 elderly controls neuropathologically proven, from the UK. 9 EOAD cases (19%) and 5 controls (2.8%) carried at least 1 rare coding variant in the genes studied
In our EOAD cohort, we identified a total of 8 rare coding variants in APP, PSEN1, and PSEN2, absent in controls
Mutations in APP, PSEN1, and PSEN2 are the only fully penetrant variants described for EOAD

Summary

Cases and controls

Our cohort was composed of 47 independent EOAD (age at onset 65 years) autopsy proven cases and 179 elderly (>60 years), unrelated controls. Three patients reported a positive family history of AD. The other patients were referred as apparently sporadic EOAD cases. All the patients and controls were Caucasian, mostly from the UK (London, Manchester, Nottingham, and Edinburgh) and to a lesser extent from North America. The average age at diagnosis was 57.7 years (range 41e64 years) for the EOAD patients and the mean age of ascertainment was 78 years (range 60e102 years) for the controls (Table 1). Written informed consent was obtained for each individual and the study was approved by the appropriate institutional review boards

Exome sequencing

Bioinformatics

Sanger sequencing

Results

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