Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

Gaël Nicolas (1, 2) , David Wallon (1, 3) , Camille Charbonnier (1) , Olivier Quenez (1, 4) , Stéphane Rousseau (1) , Anne-Claire Richard (4) , Anne Rovelet-Lecrux (1) , Sophie Coutant (5, 1, 6) , Kilan Le Guennec (1) , Delphine Bacq (7) , Jean-Guillaume Garnier (7) , Robert Olaso (7) , Anne Boland (7) , Vincent Meyer (8) , Jean-François Deleuze (7) , Hans Markus Munter (9) , Guillaume Bourque (9) , Daniel Auld (9) , Alexandre Montpetit (10) , Mark Lathrop (9) , Lucie Guyant-Maréchal (11) , Olivier Martinaud (4) , Jérémie Pariente (12) , Adeline Rollin-Sillaire (13, 14) , Florence Pasquier (15) , Isabelle Le Ber (16) , Marie Sarazin (17) , Bernard Croisile (18) , Claire Boutoleau-Bretonnière (19) , Catherine Thomas-Antérion (20) , Claire Paquet (21, 22, 23) , Mathilde Sauvee (24) , Olivier Moreaud (25, 24) , Audrey Gabelle (26) , François Sellal (27) , Mathieu Ceccaldi (28) , Ludivine Chamard (29) , Frédéric Blanc (30, 31) , Thierry Frebourg (1, 2) , Dominique Campion (1) , Didier Hannequin (1, 3)

1 GMFC - Génétique du cancer et des maladies neuropsychiatriques
2 Service de génétique [Rouen]
3 Centre Mémoire de Ressources et Recherche - CMRR [Haute-Normandie]
4 Service de neurologie [Rouen]
5 IRIB - Institute for Research and Innovation in Biomedicine
6 LITIS - Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes
7 CNG - Centre National de Génotypage
8 GENOSCOPE - Genoscope - Centre national de séquençage [Evry]
9 McGill University and Genome Quebec Innovation Centre
10 Génome Québec - Centre d'Innovation
11 Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques
12 ToNIC - Toulouse NeuroImaging Center
13 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
14 TCDV - Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046
15 Centre Mémoire de Ressources et de Recherche -CMRR [Lille-Bailleul]
16 CRICM - Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière
17 CHU Saint-Antoine [AP-HP]
18 Hôpital Neurologique Pierre Wertheimer, Service de Neurologie
19 Service de neurologie [Nantes]
20 EMC - Laboratoire d'Etude des Mécanismes Cognitifs
21 Laboratoire d'Histologie et de Biologie du Vieillissement
22 BioCANVAS / U942 - Biomarqueurs CArdioNeuroVASCulaires
23 Centre Mémoire [AP-HP Hôpital Lariboisière]
24 CMRR - Centre Mémoire de Ressources et de Recherche [Grenoble]
25 LPNC - Laboratoire de Psychologie et NeuroCognition
26 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
27 Service de neurologie
28 INS - Institut de Neurosciences des Systèmes
29 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
30 ICube - Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie
31 Département de Gériatrie [Strasbourg]

Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of late-onset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.

Domaines: Neurosciences

Gaël Nicolas, David Wallon, Camille Charbonnier, Olivier Quenez, Stéphane Rousseau, et al.. Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. European Journal of Human Genetics, 2016, 24 (5), pp.710-716. ⟨10.1038/ejhg.2015.173⟩. ⟨hal-01431285⟩