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Assessment of Mendelian and risk-factor genes in Alzheimer disease: A prospective nationwide clinical utility study and recommendations for genetic screening

2024; Elsevier BV; Volume: 26; Issue: 5 Linguagem: Inglês

10.1016/j.gim.2024.101082

1530-0366

Gaël Nicolas, Aline Zaréa, Morgane Lacour, Olivier Quenez, Stéphane Rousseau, Anne‐Claire Richard, Antoine Bonnevalle, Catherine Schramm, Robert Olaso, Florian Sandron, Anne Boland, Jean‐François Deleuze, Daniela Andriuta, Pierre Anthony, Sophie Auriacombe, Anna‐Chloé Balageas, Guillaume Ballan, Mélanie Barbay, Yannick Béjot, Serge Belliard, Marie Bénaiteau, Karim Bennys, Stéphanie Bombois, Claire Boutoleau‐Bretonnière, Pierre Branger, Jasmine Carlier, Leslie Cartz‐Piver, Pascaline Cassagnaud, Mathieu-Pierre Ceccaldi, Valérie Chauviré, Yaohua Chen, Julien Cogez, Emmanuel Cognat, Fabienne Contégal-Callier, Léa Corneille, Philippe Couratier, Benjamin Cretin, C. Crinquette, Benjamin Dauriat, Sophie Dautricourt, Vincent de La Sayette, Astrid De Liège, Didier Deffond, Florence Démurger, Vincent Deramecourt, Céline Derollez, Elsa Dionet, Martine Doco Fenzy, Julien Dumurgier, Anaïs Dutray, Frédérique Etcharry‐Bouyx, Maïté Formaglio, Audrey Gabelle, Anne Gainche-Salmon, Olivier Godefroy, Mathilde Graber, Chloé Gregoire, Stéphan Grimaldi, Julien Guéniat, Claude Guériot, Virginie Guillet‐Pichon, Sophie Haffen, Cezara-Roxana Hanta, Clémence Hardy, Geoffroy Hautecloque, Camille Heitz, Claire Hourrègue, Thérèse Jonveaux, Snejana Jurici, Lejla Koric, Pierre Krolak‐Salmon, Julien Lagarde, Hélène-Marie Lanoiselée, Brice Laurens, Isabelle Le Ber, Gwenaël Le Guyader, Amélie Leblanc, Thibaud Lebouvier, Richard A. Levy, Anaïs Lippi, Marie‐Anne Mackowiak, Éloi Magnin, Cécilia Marelli, Olivier Martinaud, Aurélien Maureille, Raffaella Migliaccio, Emilie Milongo-Rigal, Sophie Mohr, Hélène Mollion, Alexandre Morin, Julia Nivelle, Camille Noiray, Pauline Olivieri, Claire Paquet, Jérémie Pariente, Florence Pasquier, Alexandre Perron, Nathalie Philippi, Vincent Planche, Hélène Pouclet‐Courtemanche, Marie Rafiq, Adeline Rollin‐Sillaire, Carole Roué-Jagot, Dario Saracino, Marie Sarazin, Mathilde Sauvée, François Sellal, Marc Teichmann, Christel Thauvin, Quentin Thomas, Camille Tisserand, Cédric Turpinat, Laurène Van Damme, Olivier Vercruysse, Nicolas Villain, Nathalie Wagemann, Camille Charbonnier, David Wallon,

Genomics and Rare Diseases

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). 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). 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. We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure.