| Title: |
Assessment of Mendelian and risk factor genes in Alzheimer disease: a prospective nationwide clinical utility study and recommendations for genetic screening |
| Authors: |
Nicolas, Gaël; Zaréa, Aline; Lacour, Morgane; Quenez, Olivier; Rousseau, Stéphane; Richard, Anne-Claire; Bonnevalle, Antoine; Schramm, Catherine; Olaso, Robert; Sandron, Florian; Boland, Anne; Deleuze, Jean-François; Andriuta, Daniela; Anthony, Pierre; Auriacombe, Sophie; Balageas, Anna-Chloé; Ballan, Guillaume; Barbay, Mélanie; Bejot, Yannick; Belliard, Serge; Benaiteau, Marie; Bennys, Karim; Bombois, Stephanie; Boutoleau-Bretonniere, Claire; Branger, Pierre; Carlier, Jasmine; Cartz-Piver, Leslie; Cassagnaud, Pascaline; Ceccaldi, Mathieu-Pierre; Chauvire, Valérie; Chen, Yaohua; Cogez, Julien; Cognat, Emmanuel; Contegal-Callier, Fabienne; Corneille, Léa; Couratier, Philippe; Cretin, Benjamin; Crinquette, Charlotte; Dauriat, Benjamin; Dautricourt, Sophie; De La Sayette, Vincent; De Liège, Astrid; Deffond, Didier; Demurger, Florence; Deramecourt, Vincent; Derollez, Céline; Dionet, Elsa; Doco Fenzy, Martine; Dumurgier, Julien; Dutray, Anaïs; Etcharry-Bouyx, Frédérique; Formaglio, Maïté; Gabelle, Audrey; Gainche-Salmon, Anne; Godefroy, Olivier; Graber, Mathilde; Gregoire, Chloé; Grimaldi, Stephan; Gueniat, Julien; Gueriot, Claude; Guillet-Pichon, Virginie; Haffen, Sophie; Hanta, Cezara-Roxana; Hardy, Clémence; Hautecloque, Geoffroy; Heitz, Camille; Hourregue, Claire; Jonveaux, Thérèse; Jurici, Snejana; Koric, Lejla; Krolak-Salmon, Pierre; Lagarde, Julien; Lanoiselée, Hélène-Marie; Laurens, Brice; Le Ber, Isabelle; Le Guyader, Gwenaël; Leblanc, Amélie; Lebouvier, Thibaud; Levy, Richard; Lippi, Anaïs; Mackowiak, Marie-Anne; Magnin, Eloi; Marelli, Cecilia; Martinaud, Olivier; Maureille, Aurelien; Migliaccio, Raffaella; Milongo-Rigal, Emilie; Mohr, Sophie; Mollion, Hélène; Morin, Alexandre; Nivelle, Julia; Noiray, Camille; Olivieri, Pauline; Paquet, Claire; Pariente, Jérémie; Pasquier, Florence; Perron, Alexandre; Philippi, Nathalie; Planche, Vincent; Pouclet-Courtemanche, Hélène; Rafiq, Marie; Rollin-Sillaire, Adeline; Roué-Jagot, Carole; Saracino, Dario; Sarazin, Marie; Sauvée, Mathilde; Sellal, François; Teichmann, Marc; Thauvin, Christel; Thomas, Quentin; Tisserand, Camille; Turpinat, Cédric; Van Damme, Laurène; Vercruysse, Olivier; Villain, Nicolas; Wagemann, Nathalie; Charbonnier, Camille; Wallon, David |
| Contributors: |
Université de Lille; Inserm; CHU Lille; Institut du Cerveau = Paris Brain Institute ICM; CHU Pitié-Salpêtrière AP-HP; Lille Neurosciences & Cognition - U 1172 LilNCog; Equipe Alzheimer and Tauopathies - LilNCog U1172 Inserm; Centre national de référence pour les malades Alzheimer jeunes CNRMAJ |
| Publisher Information: |
Nature Publishing Group |
| Publication Year: |
2025 |
| Collection: |
LillOA (Lille Open Archive - Université de Lille) |
| Subject Terms: |
Alzheimer disease; risk variant; pathogenic variant; exome; clinical utility |
| Description: |
Purpose : To 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). Methods : We 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). Results : Twenty-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. Conclusion : We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure. ; 26;5 |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/octet-stream |
| Language: |
English |
| Relation: |
Organisation et montée en puissance d'une Infrastructure Nationale de Génomique; Genetics in Medicine; Genet Med; http://hdl.handle.net/20.500.12210/110862 |
| Availability: |
https://hdl.handle.net/20.500.12210/110862 |
| Rights: |
Attribution-NonCommercial-NoDerivs 3.0 United States ; info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.2F7394C5 |
| Database: |
BASE |