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

Autor: Nicolas G; Department of Genetics, Rouen University Hospital, Rouen, France.; Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.; CNR-MAJ, Rouen University Hospital, Rouen, France., Wallon D; Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.; CNR-MAJ, Rouen University Hospital, Rouen, France.; Department of Neurology, Rouen University Hospital, Rouen, France., Charbonnier C; Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.; CNR-MAJ, Rouen University Hospital, Rouen, France., Quenez O; Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.; CNR-MAJ, Rouen University Hospital, Rouen, France., Rousseau S; CNR-MAJ, Rouen University Hospital, Rouen, France., Richard AC; CNR-MAJ, Rouen University Hospital, Rouen, France., Rovelet-Lecrux A; Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France., Coutant S; Department of Genetics, Rouen University Hospital, Rouen, France.; Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France., Le Guennec K; Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France., Bacq D; Centre National de Génotypage, Evry, France., Garnier JG; Centre National de Génotypage, Evry, France., Olaso R; Centre National de Génotypage, Evry, France., Boland A; Centre National de Génotypage, Evry, France., Meyer V; Centre National de Génotypage, Evry, France., Deleuze JF; Centre National de Génotypage, Evry, France., Munter HM; McGill University and Génome Québec Innovation Centre, Montréal, Canada., Bourque G; McGill University and Génome Québec Innovation Centre, Montréal, Canada., Auld D; McGill University and Génome Québec Innovation Centre, Montréal, Canada., Montpetit A; McGill University and Génome Québec Innovation Centre, Montréal, Canada., Lathrop M; McGill University and Génome Québec Innovation Centre, Montréal, Canada., Guyant-Maréchal L; Department of Genetics, Rouen University Hospital, Rouen, France., Martinaud O; Department of Neurology, Rouen University Hospital, Rouen, France., Pariente J; Department of Neurology, CMRR and INSERM U825, Purpan University Hospital, Toulouse, France., Rollin-Sillaire A; CNR-MAJ; and Department of Neurology, Université de Lille, CHU, Inserm UMR-S 1171, Lille, France., Pasquier F; CNR-MAJ; and Department of Neurology, Université de Lille, CHU, Inserm UMR-S 1171, Lille, France., Le Ber I; CNR-MAJ, Pitié-Salpêtrière; and CRICM, IM2A, UMR-S975 AP-HP, University Hospital Pitié-Salpêtrière, Paris, France., Sarazin M; Department of Neurology, AP-HP, University Hospital Saint-Anne, Paris, France., Croisile B; Department of Neuropsychology, CMRR, University Hospital, Groupe Hospitalier Est, Bron, France., Boutoleau-Bretonnière C; Department of Neurology, CMRR, Nantes University Hospital, Nantes, France., Thomas-Antérion C; Department of Neurology, CMRR, University Hospital Nord, Saint Etienne, France., Paquet C; CMRR Paris Nord AP-HP, Hôpital Lariboisière, INSERM, U942, Université Paris Diderot, Sorbonne Paris Cité, UMRS 942, Paris, France., Sauvée M; CMRR, Grenoble University Hospital, Grenoble, France., Moreaud O; CMRR, Grenoble University Hospital, Grenoble, France., Gabelle A; CMRR, Gui de Chauliac Hospital, Montpellier University Hospital, Montpellier, France., Sellal F; Department of Neurology, CMRR Hôpitaux Civils de Colmar and Unité INSERM U-1118, Université de Strasbourg, Strasbourg, France., Ceccaldi M; Department of Neurology and Neuropsychology, CMRR, Timone Hospital and INSERM UMR1106, Aix-Marseille University, Marseille, France., Chamard L; Department of Neurology, CMRR, Besançon University Hospital, Besançon, France., Blanc F; CMRR Alsace, Department of Neurology, University Hospital of Strasbourg, Strasbourg, France., Frebourg T; Department of Genetics, Rouen University Hospital, Rouen, France.; Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France., Campion D; 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., Hannequin D; 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.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2016 May; Vol. 24 (5), pp. 710-6. Date of Electronic Publication: 2015 Aug 05.
DOI: 10.1038/ejhg.2015.173
Abstrakt: 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.
Databáze: MEDLINE
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