Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer's disease.
Keogh, Michael J
Al Sarraj, Safa
Alzheimer's & dementia : the journal of the Alzheimer's Association
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Nicolas, G., Acuña-Hidalgo, R., Keogh, M. J., Quenez, O., Steehouwer, M., Lelieveld, S., Rousseau, S., et al. (2018). Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer's disease.. Alzheimer's & dementia : the journal of the Alzheimer's Association, 14 (12), 1632-1639. https://doi.org/10.1016/j.jalz.2018.06.3056
INTRODUCTION. A minority of patients with sporadic early-onset Alzheimer disease (AD) exhibit de novo germline mutations in the autosomal dominant genes APP, PSEN1, or PSEN2. We hypothesized that negatively-screened patients may harbor somatic variants in these genes. METHODS. We applied an ultra-sensitive 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 AD patients (>80% exhibited an early onset, <66 years). RESULTS. We identified and confirmed by independent amplicon-based deep sequencing 9 somatic variants (allele fractions: 0.2%-10.8%): two APP, five SORL1, one NCSTN and one MARK4 variant. DISCUSSION. Two of the SORL1 variants 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.
Humans, Alzheimer Disease, Genetic Predisposition to Disease, Genes, Dominant, Mutation, Adult, Aged, Middle Aged, Female, Male
WELLCOME TRUST (103396/A/13/Z)
MRC (via University of Edinburgh) (162126)
WELLCOME TRUST (101876/Z/13/Z)
External DOI: https://doi.org/10.1016/j.jalz.2018.06.3056
This record's URL: https://www.repository.cam.ac.uk/handle/1810/283114
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/