Article
作者: Nivelle, Julia ; Ballan, Guillaume ; Boland, Anne ; Lacour, Morgane ; Noiray, Camille ; de Liège, Astrid ; Thomas, Quentin ; Van Damme, Laurène ; Richard, Anne-Claire ; Maureille, Aurelien ; Hautecloque, Geoffroy ; Wagemann, Nathalie ; Gueriot, Claude ; Charbonnier, Camille ; Branger, Pierre ; Jurici, Snejana ; Cretin, Benjamin ; Contegal-Callier, Fabienne ; Carlier, Jasmine ; Godefroy, Olivier ; Lagarde, Julien ; Lippi, Anaïs ; Heitz, Camille ; Nicolas, Gaël ; Saracino, Dario ; Quenez, Olivier ; Turpinat, Cédric ; Auriacombe, Sophie ; de la Sayette, Vincent ; Rafiq, Marie ; Wallon, David ; Hanta, Cezara-Roxana ; Ceccaldi, Mathieu-Pierre ; Bombois, Stéphanie ; Planche, Vincent ; Perron, Alexandre ; Grimaldi, Stephan ; Belliard, Serge ; Hourregue, Claire ; Leblanc, Amélie ; Cassagnaud, Pascaline ; Guillet-Pichon, Virginie ; Formaglio, Maïté ; Martinaud, Olivier ; Marelli, Cecilia ; Vercruysse, Olivier ; Gregoire, Chloé ; Andriuta, Daniela ; Lanoiselée, Hélène-Marie ; Cogez, Julien ; Cartz-Piver, Leslie ; Gueniat, Julien ; Derollez, Céline ; Graber, Mathilde ; Villain, Nicolas ; Levy, Richard ; Bennys, Karim ; Paquet, Claire ; Hardy, Clémence ; Doco Fenzy, Martine ; Zaréa, Aline ; Le Ber, Isabelle ; Koric, Lejla ; Sauvée, Mathilde ; Tisserand, Camille ; Rousseau, Stéphane ; Crinquette, Charlotte ; Corneille, Léa ; Cognat, Emmanuel ; Chauviré, Valérie ; Mackowiak, Marie-Anne ; Bonnevalle, Antoine ; Gabelle, Audrey ; Pariente, Jérémie ; Gainche-Salmon, Anne ; Deleuze, Jean-François ; Roué-Jagot, Carole ; Demurger, Florence ; Chen, Yaohua ; Le Guyader, Gwenaël ; Mohr, Sophie ; Morin, Alexandre ; Couratier, Philippe ; Béjot, Yannick ; Magnin, Eloi ; Laurens, Brice ; Anthony, Pierre ; Milongo-Rigal, Emilie ; Balageas, Anna-Chloé ; Pasquier, Florence ; Lebouvier, Thibaud ; Deramecourt, Vincent ; Sellal, François ; Benaiteau, Marie ; Sandron, Florian ; Mollion, Hélène ; Dionet, Elsa ; Dautricourt, Sophie ; Rollin-Sillaire, Adeline ; Krolak-Salmon, Pierre ; Dumurgier, Julien ; Jonveaux, Thérèse ; Olivieri, Pauline ; Olaso, Robert ; Thauvin, Christel ; Teichmann, Marc ; Barbay, Mélanie ; Dutray, Anaïs ; Dauriat, Benjamin ; Etcharry-Bouyx, Frédérique ; Deffond, Didier ; Schramm, Catherine ; Sarazin, Marie ; Haffen, Sophie ; Pouclet-Courtemanche, Hélène ; Philippi, Nathalie ; Migliaccio, Raffaella ; Boutoleau-Bretonnière, Claire
PURPOSETo assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD).METHODSWe included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients. We built a framework for risk variant interpretation and risk gradation and assessed the detection rates among early-onset AD (EOAD, age of onset (AOO) ≤65 years, n = 608) depending on AOO and pedigree structure and late-onset AD (66 < AOO < 75, n = 92).RESULTSTwenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20 of 21 affected APP, PSEN1, or PSEN2. LP/P variant detection rates in EOAD ranged from 1.7% to 11.6% based on AOO and pedigree structure. Risk factors were found in 69.5% of the remaining 679 patients, including 83 (12.2%) being heterozygotes for rare risk variants, in decreasing order of frequency, in TREM2, ABCA7, ATP8B4, SORL1, and ABCA1, including 5 heterozygotes for multiple rare risk variants, suggesting non-monogenic inheritance, even in some autosomal-dominant-like pedigrees.CONCLUSIONWe suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure.