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.
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Acknowledgements
We are grateful to Tracey Avequin for her help in editing the manuscript. This study was funded by grants from the Clinical Research Hospital Program from the French Ministry of Health (GMAJ, PHRC 2008/067) to Didier Hannequin and Dominique Campion, the CNR-MAJ and the JPND PERADES. The funding sources had no specific roles. CNR-MAJ collaborators: Didier Hannequin, Dominique Campion, David Wallon, Olivier Martinaud, Gaël Nicolas (Centre Hospitalo-Universitaire (CHU), Rouen); Olivier Godefroy (CHU Amiens); Frédérique Etcharry-Bouyx, Valérie Chauviré (CHU Angers); Ludivine Chamard, Eric Berger, Eloi Magnin (CHU Besancon); Jean-Francois Dartigues, Sophie Auriacombe (CHU Bordeaux); Vincent de la Sayette, Fausto Viader (CHU Caen); Dominique Castan (CH Castres), Elsa Dionet (CHU Clermont-Ferrand); Francois Sellal (CH Colmar); Olivier Rouaud, Christel Thauvin (CHU Dijon); Olivier Moreaud, Mathilde Sauvée (CHU Grenoble); Adeline Rollin-Sillaire, Stéphanie Bombois, Marie-Anne Mackowiak, Vincent Deramecourt, Florence Pasquier (CHU Lille); Maïté Formaglio, Hélène Mollion, Isabelle Roullet-Solignac, Alain Vighetto, Bernard Croisile (CHU Lyon); Mira Didic, Olivier Félician, Lejla Koric, Mathieu Ceccaldi (CHU Marseille); Audrey Gabelle, Cecilia Marelli, Jacques Touchon, Pierre Labauge (CHU Montpellier); Thérèse Jonveaux (CHU Nancy); Martine Vercelletto, Claire Boutoleau-Bretonnière (CHU Nantes); Giovanni Castelnovo (CHU Nimes); David Renaud, Philippe Robert (CHU de Nice); Claire Paquet, Julien Dumurgier, Jacques Hugon (CHU Lariboisière, Paris); Agnès Michon, Isabelle Le Ber, Bruno Dubois, Charles Duyckaerts (CHU La Salpêtrière, Paris); Foucauld De Boisgueheneuc (CHU Poitiers); Serge Belliard (CHU Rennes); Serge Bakchine (CHU de Reims); Marie-Odile Barrellon, Bernard Laurent (CHU Saint-Etienne); Frédéric Blanc, Christine Tranchant (CHU Strasbourg); Jérémie Pariente, Michèle Puel (CHU Toulouse); and Caroline Hommet, Karl Mondon (CHU Tours).
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Nicolas, G., Wallon, D., Charbonnier, C. et al. Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet 24, 710–716 (2016). https://doi.org/10.1038/ejhg.2015.173
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DOI: https://doi.org/10.1038/ejhg.2015.173
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