| Affiliation: | 1. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands;2. Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France;3. Max Planck Institute for Molecular Genetics, RG Development & Disease, Berlin, Germany;4. Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK;5. MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0XY, UK;6. Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Neuropathology, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France;7. Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, NE4 5PL, UK;8. National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK;9. Department of Neuropathology, John Radcliffe Hospital, Oxford, OX3 9DU, UK;10. Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King''s College London, London, SE5 8AF, UK;11. Department of research, Rouvray Psychiatric Hospital, Sotteville-lès-Rouen, France;12. Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics, Department of Neurology and CNR-MAJ, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France;13. Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Neurology and CNR-MAJ, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France;14. Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, United Kingdom;15. Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands |
| Abstract: | IntroductionA 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.MethodsWe 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).ResultsWe 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.DiscussionTwo 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. |
