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

Gaël Nicolas (1, 2) , Rocio Acuna-Hidalgo (3) , Michael Keogh (4) , Olivier Quenez (2) , Marloes Steehouwer (5) , Stefan H. Lelieveld (5) , Stéphane Rousseau (2) , Anne-Claire Richard (2) , Manon Oud (5) , Florent Marguet (6, 2) , Annie Laquerrière (7, 2) , Chris Morris (8) , Johannes Attems (8) , Colin Smith (9) , Olaf Ansorge (10) , Safa Al Sarraj (11) , Thierry Frebourg (2) , Dominique Campion (12, 2) , Didier Hannequin (13, 2) , David Wallon (13, 2) , Christian Gilissen (3) , Patrick Chinnery (14) , Joris A Veltman (3) , Alexander Hoischen (3)

1 UNIROUEN UFR Santé - UNIROUEN - UFR Santé
2 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
3 Radboud University Medical Center [Nijmegen]
4 Department of Clinical Neurosciences [Cambridge]
5 Department of Human Genetics [Nijmegen]
6 Département de Pathologie [CHU Rouen]
7 Service d'Anatomie et Cytologie Pathologique [CHU Rouen]
8 ION - Institute of Neuroscience [Newcastle]
9 BRE/Edinburgh - Building Research Establishment
10 John Radcliffe Hospital [Oxford University Hospital]
11 King‘s College London
12 Department of Research, Centre hospitalier du Rouvray, Sotteville-lès-Rouen, France
13 Service de neurologie [Rouen]
14 Mitochondrial Research Group

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.

Mots clés: Alzheimer; Mutation; Post‐zygotic; Mosaicism; Prion‐like; Post-zygotic; Prion-like

Domaines: Sciences du Vivant [q-bio]

Gaël Nicolas, Rocio Acuna-Hidalgo, Michael Keogh, Olivier Quenez, Marloes Steehouwer, et al.. Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer's disease. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 2018, 14 (12), pp.1632-1639. ⟨10.1016/j.jalz.2018.06.3056⟩. ⟨hal-02540061⟩