NICOLAS, Gael; ZAREA, Aline; LACOUR, Morgane; QUENEZ, Olivier; ROUSSEAU, Stephane; RICHARD, Anne-Claire; BONNEVALLE, Antoine; SCHRAMM, Catherine; OLASO, Robert; SANDRON, Florian; BOLAND, Anne; DELEUZE, Jean-Francois; ANDRIUTA, Daniela; ANTHONY, Pierre; AURIACOMBE, Sophie; BALAGEAS, Anna-Chloe; BALLAN, Guillaume; BARBAY, Melanie; 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, Valerie; CHEN, Yaohua; COGEZ, Julien; COGNAT, Emmanuel; CONTEGAL-CALLIER, Fabienne; CORNEILLE, Lea; COURATIER, Philippe; CRETIN, Benjamin; CRINQUETTE, Charlotte; DAURIAT, Benjamin; DAUTRICOURT, Sophie; DE LA SAYETTE, Vincent; DE LIEGE, Astrid; DEFFOND, Didier; DEMURGER, Florence; DERAMECOURT, Vincent; DEROLLEZ, Celine; DIONET, Elsa; DOCO FENZY, Martine; DUMURGIER, Julien; DUTRAY, Anais; ETCHARRY-BOUYX, Frederique; FORMAGLIO, Maite; GABELLE, Audrey; GAINCHE-SALMON, Anne; GODEFROY, Olivier; GRABER, Mathilde; GREGOIRE, Chloe; GRIMALDI, Stephan; GUENIAT, Julien; GUERIOT, Claude; GUILLET-PICHON, Virginie; HAFFEN, Sophie; HANTA, Cezara-Roxana; HARDY, Clemence; HAUTECLOQUE, Geoffroy; HEITZ, Camille; HOURREGUE, Claire; JONVEAUX, Therese; JURICI, Snejana; KORIC, Lejla; KROLAK-SALMON, Pierre; LAGARDE, Julien; LANOISELEE, Helene-Marie; LAURENS, Brice; LE BER, Isabelle; LE GUYADER, Gwenael; LEBLANC, Amelie; LEBOUVIER, Thibaud; LEVY, Richard; LIPPI, Anais; MACKOWIAK, Marie-Anne; MAGNIN, Eloi; MARELLI, Cecilia; MARTINAUD, Olivier; MAUREILLE, Aurelien; MIGLIACCIO, Raffaella; MILONGO-RIGAL, Emilie; MOHR, Sophie; MOLLION, Helene; MORIN, Alexandre; NIVELLE, Julia; NOIRAY, Camille; OLIVIERI, Pauline; PAQUET, Claire; PARIENTE, Jeremie; PASQUIER, Florence; PERRON, Alexandre; PHILIPPI, Nathalie; PLANCHE, Vincent; POUCLET-COURTEMANCHE, Helene; RAFIQ, Marie; ROLLIN-SILLAIRE, Adeline; ROUE-JAGOT, Carole; SARACINO, Dario; SARAZIN, Marie; SAUVEE, Mathilde; SELLAL, Francois; TEICHMANN, Marc; THAUVIN, Christel; THOMAS, Quentin; TISSERAND, Camille; TURPINAT, Cedric; VAN DAMME, Laurene; VERCRUYSSE, Olivier; VILLAIN, Nicolas; WAGEMANN, Nathalie; CHARBONNIER, Camille; WALLON, David

doi:10.1016/j.gim.2024.101082

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Genetics in Medicine. 2024-01-24p. 101082

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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 (LOAD, 66<AOO<75, n=92). RESULTS: Twenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20/21 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.< Réduire

Mots clés en anglais

Alzheimer disease

risk variant

pathogenic variant

exome

clinical utility

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https://oskar-bordeaux.fr/handle/20.500.12278/188297

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http://dx.doi.org/10.1016/j.gim.2024.101082

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Organisation et montée en puissance d'une Infrastructure Nationale de Génomique

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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

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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

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Résumé en anglais

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DOI

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Unités de recherche