Assessment of Mendelian and risk-factor genes in Alzheimer disease: A prospective nationwide clinical utility study and recommendations for genetic screening.
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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, Béjot Yannick, Belliard Serge, Benaiteau Marie, Bennys Karim, Bombois Stéphanie, Boutoleau-Bretonnière Claire, Branger Pierre, Carlier Jasmine, Cartz-Piver Leslie, Cassagnaud Pascaline, Ceccaldi Mathieu-Pierre, Chauviré 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
Аннотация
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.