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Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer's disease

Lookup NU author(s): Dr Christopher Morris, Professor Johannes Attems



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


© 2018 The Authors Introduction: A minority of patients with sporadic early-onset Alzheimer's disease (AD) exhibit de novo germ line mutations in the autosomal dominant genes such as APP, PSEN1, or PSEN2. We hypothesized that negatively screened patients may harbor somatic variants in these genes. Methods: We applied an ultrasensitive approach based on single-molecule molecular inversion probes followed by deep next generation sequencing of 11 genes to 100 brain and 355 blood samples from 445 sporadic patients with AD (>80% exhibited an early onset, <66 years). Results: We identified and confirmed nine somatic variants (allele fractions: 0.2%–10.8%): two APP, five SORL1, one NCSTN, and one MARK4 variants by independent amplicon-based deep sequencing. Discussion: Two of the SORL1 variant might have contributed to the disease, the two APP variants were interpreted as likely benign and the other variants remained of unknown significance. Somatic variants in the autosomal dominant AD genes may not be a common cause of sporadic AD, including early onset cases.

Publication metadata

Author(s): Nicolas G, Acuna-Hidalgo R, Keogh MJ, Quenez O, Steehouwer M, Lelieveld S, Rousseau S, Richard A-C, Oud MS, Marguet F, Laquerriere A, Morris CM, Attems J, Smith C, Ansorge O, Al Sarraj S, Frebourg T, Campion D, Hannequin D, Wallon D, Gilissen C, Chinnery PF, Veltman JA, Hoischen A

Publication type: Article

Publication status: Published

Journal: Alzheimer's and Dementia

Year: 2018

Volume: 14

Issue: 12

Pages: 1632-1639

Print publication date: 01/12/2018

Online publication date: 13/08/2018

Acceptance date: 02/04/2018

Date deposited: 29/10/2018

ISSN (print): 1552-5260

ISSN (electronic): 1552-5279

Publisher: Elsevier Inc.


DOI: 10.1016/j.jalz.2018.06.3056


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Funder referenceFunder name
101876/Z/13/ZWellcome Trust
13044Bloodwise (Formerly Leukaemia and Lymphoma Research)
13044Medical Research Council (MRC)
Alzheimer's Society and Alzheimer's Research UK
NIHR Newcastle Biomedical Research Center
Radboud University Medical Center