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 Singleton; John Hardy; ARUK Consortium

doi:10.1016/j.neurobiolaging.2014.04.026

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

29 Citations (Scopus)

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).

Original language	English
Article number	2422.e13-2422.e16
Number of pages	4
Journal	Neurobiology of Aging
Volume	35
Issue number	10
DOIs	https://doi.org/10.1016/j.neurobiolaging.2014.04.026
Publication status	Published - Oct 2014

Keywords

Early-onset Alzheimer's disease
APP
PSEN1
PSEN2
British cohort
PRECURSOR PROTEIN GENE
GENERATION

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Sassi, C., Guerreiro, R., Gibbs, R., Ding, J., Lupton, M. K., Troakes, C., Lunnon, K., Al-Sarraj, S., Brown, K. S., Medway, C., Lord, J., Turton, J., Mann, D., Snowden, J., Neary, D., Harris, J., Bras, J., Morgan, K., Powell, J. F., ... ARUK Consortium (2014). Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease. Neurobiology of Aging, 35(10), Article 2422.e13-2422.e16. https://doi.org/10.1016/j.neurobiolaging.2014.04.026

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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).",

keywords = "Early-onset Alzheimer's disease, APP, PSEN1, PSEN2, British cohort, PRECURSOR PROTEIN GENE, GENERATION",

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

year = "2014",

month = oct,

doi = "10.1016/j.neurobiolaging.2014.04.026",

language = "English",

volume = "35",

journal = "Neurobiology of Aging",

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Sassi, C, Guerreiro, R, Gibbs, R, Ding, J, Lupton, MK, Troakes, C , Lunnon, K , Al-Sarraj, S, Brown, KS, Medway, C, Lord, J, Turton, J, Mann, D, Snowden, J, Neary, D, Harris, J, Bras, J, Morgan, K, Powell, JF, Singleton, A, Hardy, J & ARUK Consortium 2014, 'Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease', Neurobiology of Aging, vol. 35, no. 10, 2422.e13-2422.e16. https://doi.org/10.1016/j.neurobiolaging.2014.04.026

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T1 - Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease

AU - Sassi, Celeste

AU - Guerreiro, Rita

AU - Gibbs, Raphael

AU - Ding, Jinhui

AU - Lupton, Michelle K.

AU - Troakes, Claire

AU - Lunnon, Katie

AU - Al-Sarraj, Safa

AU - Brown, Kristelle S.

AU - Medway, Chirstopher

AU - Lord, Jenny

AU - Turton, James

AU - Mann, David

AU - Snowden, Julie

AU - Neary, David

AU - Harris, Jeniffer

AU - Bras, Jose

AU - Morgan, Kevin

AU - Powell, John F.

AU - Singleton, Andrew

AU - Hardy, John

AU - ARUK Consortium

PY - 2014/10

Y1 - 2014/10

N2 - 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).

AB - 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).

KW - Early-onset Alzheimer's disease

KW - APP

KW - PSEN1

KW - PSEN2

KW - British cohort

KW - PRECURSOR PROTEIN GENE

KW - GENERATION

U2 - 10.1016/j.neurobiolaging.2014.04.026

DO - 10.1016/j.neurobiolaging.2014.04.026

M3 - Article

SN - 0197-4580

VL - 35

JO - Neurobiology of Aging

JF - Neurobiology of Aging

IS - 10

M1 - 2422.e13-2422.e16

ER -

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

Abstract

Keywords

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