Journal
ALZHEIMERS & DEMENTIA
Volume 14, Issue 12, Pages 1632-1639Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jalz.2018.06.3056
Keywords
Mosaicism; Post-zygotic; Mutation; Alzheimer; Prion-like
Categories
Funding
- Radboud University Medical Center
- Netherlands Organization for Scientific Research [918-15-667]
- UK Medical Research Council [G0400074, 13044]
- Medical Research Council Mitochondrial Biology Unit [MC_UP_1501/2]
- Evelyn Trust
- Medical Research Council (UK) Center for Translational Muscle Disease Research [G0601943]
- EU FP7 TIRCON
- National Institute for Health Research (NIHR) Biomedical ResearchCenter based at Cambridge University Hospitals NHS Foundation Trust
- University of Cambridge
- Alzheimer's Society
- Alzheimer's Research UK
- NIHR Newcastle Biomedical Research Center
- CNR-MAJ
- MRC [G0601943, G0400074, G0900652, G0502157, G1100540] Funding Source: UKRI
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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. (C) 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.
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