title: Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons.
abstract: 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.
authors.affiliation: Department of Genetics, Rouen University Hospital, Rouen, France.|Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.
authors.forename: Gaël
authors.initials: G
authors.lastname: Nicolas
authors.affiliation: Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.|Department of Neurology, Rouen University Hospital, Rouen, France.
authors.forename: David
authors.initials: D
authors.lastname: Wallon
authors.affiliation: Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Charbonnier
authors.affiliation: Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Quenez
authors.affiliation: CNR-MAJ, Rouen University Hospital, Rouen, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Rousseau
authors.affiliation: CNR-MAJ, Rouen University Hospital, Rouen, France.
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Richard
authors.affiliation: Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Rovelet-Lecrux
authors.affiliation: Department of Genetics, Rouen University Hospital, Rouen, France.|Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Coutant
authors.affiliation: Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.
authors.forename: Kilan
authors.initials: K
authors.lastname: Le Guennec
authors.affiliation: Centre National de Génotypage, Evry, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Bacq
authors.affiliation: Centre National de Génotypage, Evry, France.
authors.forename: Jean-Guillaume
authors.initials: JG
authors.lastname: Garnier
authors.affiliation: Centre National de Génotypage, Evry, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Olaso
authors.affiliation: Centre National de Génotypage, Evry, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Boland
authors.affiliation: Centre National de Génotypage, Evry, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Meyer
authors.affiliation: Centre National de Génotypage, Evry, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Deleuze
authors.affiliation: McGill University and Génome Québec Innovation Centre, Montréal, Canada.
authors.forename: Hans Markus
authors.identifier: http://orcid.org/0000-0002-3165-2840
authors.initials: HM
authors.lastname: Munter
authors.affiliation: McGill University and Génome Québec Innovation Centre, Montréal, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bourque
authors.affiliation: McGill University and Génome Québec Innovation Centre, Montréal, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Auld
authors.affiliation: McGill University and Génome Québec Innovation Centre, Montréal, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Montpetit
authors.affiliation: McGill University and Génome Québec Innovation Centre, Montréal, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: Department of Genetics, Rouen University Hospital, Rouen, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Guyant-Maréchal
authors.affiliation: Department of Neurology, Rouen University Hospital, Rouen, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Martinaud
authors.affiliation: Department of Neurology, CMRR and INSERM U825, Purpan University Hospital, Toulouse, France.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Pariente
authors.affiliation: CNR-MAJ; and Department of Neurology, Université de Lille, CHU, Inserm UMR-S 1171, Lille, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Rollin-Sillaire
authors.affiliation: CNR-MAJ; and Department of Neurology, Université de Lille, CHU, Inserm UMR-S 1171, Lille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Pasquier
authors.affiliation: CNR-MAJ, Pitié-Salpêtrière; and CRICM, IM2A, UMR-S975 AP-HP, University Hospital Pitié-Salpêtrière, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Ber
authors.affiliation: Department of Neurology, AP-HP, University Hospital Saint-Anne, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Sarazin
authors.affiliation: Department of Neuropsychology, CMRR, University Hospital, Groupe Hospitalier Est, Bron, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Croisile
authors.affiliation: Department of Neurology, CMRR, Nantes University Hospital, Nantes, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Boutoleau-Bretonnière
authors.affiliation: Department of Neurology, CMRR, University Hospital Nord, Saint Etienne, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Thomas-Antérion
authors.affiliation: CMRR Paris Nord AP-HP, Hôpital Lariboisière, INSERM, U942, Université Paris Diderot, Sorbonne Paris Cité, UMRS 942, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Paquet
authors.affiliation: CMRR, Grenoble University Hospital, Grenoble, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Sauvée
authors.affiliation: CMRR, Grenoble University Hospital, Grenoble, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Moreaud
authors.affiliation: CMRR, Gui de Chauliac Hospital, Montpellier University Hospital, Montpellier, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Gabelle
authors.affiliation: Department of Neurology, CMRR Hôpitaux Civils de Colmar and Unité INSERM U-1118, Université de Strasbourg, Strasbourg, France.
authors.forename: François
authors.initials: F
authors.lastname: Sellal
authors.affiliation: Department of Neurology and Neuropsychology, CMRR, Timone Hospital and INSERM UMR1106, Aix-Marseille University, Marseille, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Ceccaldi
authors.affiliation: Department of Neurology, CMRR, Besançon University Hospital, Besançon, France.
authors.forename: Ludivine
authors.initials: L
authors.lastname: Chamard
authors.affiliation: CMRR Alsace, Department of Neurology, University Hospital of Strasbourg, Strasbourg, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Blanc
authors.affiliation: Department of Genetics, Rouen University Hospital, Rouen, France.|Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Frebourg
authors.affiliation: Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.|Department of Research, Rouvray Psychiatric Hospital, Sotteville-lès-Rouen, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
authors.affiliation: Department of Genetics, Rouen University Hospital, Rouen, France.|Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.|Department of Neurology, Rouen University Hospital, Rouen, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Hannequin
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D016022:Case-Control Studies; D059472:Exome; D005260:Female; D005820:Genetic Testing / Q000379:methods* / Q000592:standards; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D053764:Presenilin-1 / Q000235:genetics; D053766:Presenilin-2 / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000235:genetics
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2