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authors
- 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
keywords
- Alzheimer disease
- Risk variant
- Pathogenic variant
- Exome
- Clinical utility
document type
ART
abstract
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.
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