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

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 Benaiteau; 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 Contegal-Callier; Léa Corneille; Philippe Couratier; Benjamin Cretin; Charlotte Crinquette; Benjamin Dauriat; Sophie Dautricourt; Vincent de la Sayette; Astrid de Liège; Didier Deffond; Florence Demurger; 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; Stephan Grimaldi; Julien Gueniat; Claude Gueriot; Virginie Guillet-Pichon; Sophie Haffen; Cezara-Roxana Hanta; Clémence Hardy; Geoffroy Hautecloque; Camille Heitz; Claire Hourregue; 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 Levy; Anaïs Lippi; Marie-Anne Mackowiak; Eloi Magnin; Cecilia Marelli; Olivier Martinaud; Aurelien 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

doi:10.1016/j.gim.2024.101082

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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

Gaël Nicolas, Aline Zaréa, Morgane Lacour, Olivier Quenez, Stéphane Rousseau, Anne-Claire Richard, Antoine Bonnevalle, Catherine Schramm, Robert Olaso, Florian Sandron, …

Genetics in medicine, Vol.26(5), p.101082

01/05/2024

DOI: https://doi.org/10.1016/j.gim.2024.101082

PMID: 38281098

Résumé

Alzheimer disease

Clinical utility

Exome

Pathogenic variant

Risk variant

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.

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Titre: Assessment of Mendelian and risk-factor genes in Alzheimer disease: A prospective nationwide clinical utility study and recommendations for genetic screening
Créateurs - sans rôle: Gaël Nicolas - Inserm
Aline Zaréa - Inserm
Morgane Lacour - Inserm
Olivier Quenez - Inserm
Stéphane Rousseau - Inserm
Anne-Claire Richard - Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Department of Genetics and CNRMAJ, F-76000 Rouen, France
Antoine Bonnevalle - Inserm
Catherine Schramm - Inserm
Robert Olaso - Centre National de Recherche en Génomique Humaine
Florian Sandron - Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), Evry, France
Anne Boland - Centre National de Recherche en Génomique Humaine
Jean-François Deleuze - Centre National de Recherche en Génomique Humaine
Daniela Andriuta - Laboratoire de neurosciences fonctionnelles et pathologies
Pierre Anthony - Department of Neurology, Hôpitaux Civils de Colmar, F-68000 Colmar, France
Sophie Auriacombe - Institut des Maladies Neurodégénératives
Anna-Chloé Balageas - Centre Mémoire Ressources et Recherche, CHRU de Tours, Tours, France
Guillaume Ballan - Centre Hospitalier de la Côte Basque
Mélanie Barbay - Laboratoire de neurosciences fonctionnelles et pathologies
Yannick Béjot - Department of Neurology, University Hospital of Dijon, University of Burgundy, Dijon, France
Serge Belliard - Unité de recherche 1077 INSERM-EPHE-UNICAEN Neuropsychologie & Imagerie de la Mémoire Humaine (NIMH), Caen, France
Marie Benaiteau - Centre Hospitalier Universitaire de Toulouse
Karim Bennys - Memory Ressources Research Center, Department of Neurology, University Hospital of Montpellier, Montpellier, France
Stéphanie Bombois - Institut du Cerveau
Claire Boutoleau-Bretonnière - Inserm
Pierre Branger - Department of Neurology, Caen University Hospital, Caen, France
Jasmine Carlier - Neurology Department, Hôpital Pierre-Paul Riquet, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
Leslie Cartz-Piver - Memory Ressources Research Center, Department of Neurology, University Hospital of Limoges, France Inserm U1094, IRD U270, EPIMACT, Université of Limoges, Limoges, France
Pascaline Cassagnaud - CHU Lille, Memory Center, CNRMAJ 59000 Lille, France
Mathieu-Pierre Ceccaldi - Institute of Neurophysiopathology UMR 7051 Aix Marseille Université & Assistance Publique de Marseille, Marseille, France
Valérie Chauviré - CMRR, CRMR Neurogénétique, Service de Neurologie, CHU d'ANGERS, Angers, France
Yaohua Chen - Univ Lille, CHU Lille, Inserm 1172, Memory center, CNRMAJ, LiCEND, Labex DistAlz 59000 Lille, France
Julien Cogez - Department of Neurology, Caen University Hospital, Caen, France
Emmanuel Cognat - Assistance Publique – Hôpitaux de Paris
Fabienne Contegal-Callier - Hospices Civils de Beaune, Consultation mémoire, Beaune, France
Léa Corneille - Institute of Neurophysiopathology UMR 7051 Aix Marseille Université & Assistance Publique de Marseille, Marseille, France
Philippe Couratier - CMRR Limoges, Service de Neurologie CHU Limoges, Limoges, France
Benjamin Cretin - CMRR d'Alsace, Service de Neurologie, CHU Strasbourg, Strasbourg, France
Charlotte Crinquette - CHU Lille, Memory Center, CNRMAJ 59000 Lille, France
Benjamin Dauriat - Hôpital Mère-Enfant
Sophie Dautricourt - CMRR Lyon, Department of Neurology, University Hospital of Lyon, Hospices Civils de Lyon, Lyon, France
Vincent de la Sayette - Department of Neurology, Caen University Hospital, Caen, France
Astrid de Liège - Service de Neurologie, APHP, Hôpital Avicenne, Université Sorbonne Paris Nord, Bobigny, France
Didier Deffond - CMRR Clermont-Ferrand, Service de Neurologie, CHU Clermont-Ferrand, Clermont-Ferrand, France
Florence Demurger - Service de génétique, CHBA, Vannes, France
Vincent Deramecourt - Univ Lille, CHU Lille, Inserm 1172, Memory center, CNRMAJ, LiCEND, Labex DistAlz 59000 Lille, France
Céline Derollez - CHU Lille, Memory Center, CNRMAJ 59000 Lille, France
Elsa Dionet - CMRR Clermont-Ferrand, Service de Neurologie, CHU Clermont-Ferrand, Clermont-Ferrand, France
Martine Doco Fenzy - Nantes Université, CHU Nantes, CNRS, INSERM, l’institut du thorax, Nantes, France
Julien Dumurgier - Assistance Publique – Hôpitaux de Paris
Anaïs Dutray - Service de Neurologie, Centre Hospitalier Perpignan, Perpignan, France
Frédérique Etcharry-Bouyx - CMRR, CRMR Neurogénétique, Service de Neurologie, CHU d'ANGERS, Angers, France
Maïté Formaglio - CMRR Lyon, Department of Neurology, University Hospital of Lyon, Hospices Civils de Lyon, Lyon, France
Audrey Gabelle - Memory Ressources Research Center, Department of Neurology, University Hospital of Montpellier, Montpellier, France
Anne Gainche-Salmon - Centre Hospitalier Universitaire de Rennes
Olivier Godefroy - Laboratoire de neurosciences fonctionnelles et pathologies
Mathilde Graber - Centre mémoire ressources et recherche, CHU Dijon, Dijon, France
Chloé Gregoire - CHU de Bordeaux, Pôle de Neurosciences Cliniques, Centre Mémoire de Ressources et de Recherche, Bordeaux, France
Stephan Grimaldi - Institute of Neurophysiopathology UMR 7051 Aix Marseille Université & Assistance Publique de Marseille, Marseille, France
Julien Gueniat - Centre mémoire ressources et recherche, CHU Dijon, Dijon, France
Claude Gueriot - Institute of Neurophysiopathology UMR 7051 Aix Marseille Université & Assistance Publique de Marseille, Marseille, France
Virginie Guillet-Pichon - CMRR, CRMR Neurogénétique, Service de Neurologie, CHU d'ANGERS, Angers, France
Sophie Haffen - Centre mémoire Recherche Ressources, Service de Neurologie, CHU Besançon, Besançon, France
Cezara-Roxana Hanta - Centre Mémoire Ressources et Recherche Haute Bretagne, CHU Rennes, Rennes, France
Clémence Hardy - Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Department of Neurology and CNRMAJ, F-76000 Rouen, France
Geoffroy Hautecloque - Department of Neurology, Hôpitaux Civils de Colmar, F-68000 Colmar, France
Camille Heitz - Institut du Cerveau
Claire Hourregue - Cognitive Neurology Center, AP-HP.Nord, Site Lariboisière Fernand-Widal, Paris, France
Thérèse Jonveaux - Centre Mémoire de Ressources et de Recherche de Lorraine Service de Neurologie CHRU Nancy, Nancy, France
Snejana Jurici - Consultation Mémoire, Service de Gériatrie, Centre Hospitalier Perpignan, Perpignan, France
Lejla Koric - Institute of Neurophysiopathology UMR 7051 Aix Marseille Université & Assistance Publique de Marseille, Marseille, France
Pierre Krolak-Salmon - CMRR Lyon, Department of Neurology, University Hospital of Lyon, Hospices Civils de Lyon, Lyon, France
Julien Lagarde - Department of Neurology of Memory and Language, GHU Paris Psychiatrie & Neurosciences, Hôpital Sainte Anne, F-75014, Paris, France
Hélène-Marie Lanoiselée - Service de neurologie, Centre Hospitalier Régional d'Orléans, Orléans, France
Brice Laurens - CHU de Bordeaux, Pôle de Neurosciences Cliniques, Centre Mémoire de Ressources et de Recherche, Bordeaux, France
Isabelle Le Ber - Institut du Cerveau
Gwenaël Le Guyader - Service de Génétique, CHU Poitiers, 86022 Poitiers Cedex, France
Amélie Leblanc - Consultations neurologiques, HIA Clermont-Tonnerre, Brest, France
Thibaud Lebouvier - Université de Lille
Richard Levy - Institut du Cerveau
Anaïs Lippi - Service de Neurologie, Hopital Gui de Chauliac, CHU de Montpellier, Montpellier, France
Marie-Anne Mackowiak - CHU Lille, Memory Center, CNRMAJ 59000 Lille, France
Eloi Magnin - Université de franche-comté
Cecilia Marelli - Service de Neurologie, Hopital Gui de Chauliac, CHU de Montpellier, Montpellier, France
Olivier Martinaud - Department of Neurology, Caen University Hospital, Caen, France
Aurelien Maureille - CHU Lille, Memory Center, CNRMAJ 59000 Lille, France
Raffaella Migliaccio - Institut du Cerveau
Emilie Milongo-Rigal - Neurology Department, Hôpital Pierre-Paul Riquet, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
Sophie Mohr - Centre mémoire ressources et recherche, CHU Dijon, Dijon, France
Hélène Mollion - CMRR Lyon, Department of Neurology, University Hospital of Lyon, Hospices Civils de Lyon, Lyon, France
Alexandre Morin - Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Department of Neurology and CNRMAJ, F-76000 Rouen, France
Julia Nivelle - CH Ales Cévennes, Alès, France
Camille Noiray - GHU Paris psychiatrie & neurosciences
Pauline Olivieri - Department of Neurology of Memory and Language, GHU Paris Psychiatrie & Neurosciences, Hôpital Sainte Anne, F-75014, Paris, France
Claire Paquet - Assistance Publique – Hôpitaux de Paris
Jérémie Pariente - Centre Hospitalier Universitaire de Toulouse
Florence Pasquier - Univ Lille, CHU Lille, Inserm 1172, Memory center, CNRMAJ, LiCEND, Labex DistAlz 59000 Lille, France
Alexandre Perron - Department of Neurology, Hôpitaux Civils de Colmar, F-68000 Colmar, France
Nathalie Philippi - CMRR d'Alsace, Service de Neurologie, CHU Strasbourg, Strasbourg, France
Vincent Planche - Institut des Maladies Neurodégénératives
Hélène Pouclet-Courtemanche - Université de Nantes
Marie Rafiq - Neurology Department, Hôpital Pierre-Paul Riquet, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
Adeline Rollin-Sillaire - CHU Lille, Memory Center, CNRMAJ 59000 Lille, France
Carole Roué-Jagot - Department of Neurology of Memory and Language, GHU Paris Psychiatrie & Neurosciences, Hôpital Sainte Anne, F-75014, Paris, France
Dario Saracino - Sorbonne Université, INSERM U1127, CNRS 7235, Institut du Cerveau - ICM, Paris, France
Marie Sarazin - Department of Neurology of Memory and Language, GHU Paris Psychiatrie & Neurosciences, Hôpital Sainte Anne, F-75014, Paris, France
Mathilde Sauvée - Centre Mémoire de Ressources et de Recherche, Pôle PReNeLe, CHU Grenoble Alpes CS 10226, 38043 Grenoble Cedex 9, France
François Sellal - Hopitaux Civils de Colmar
Marc Teichmann - Pitié-Salpêtrière Hospital
Christel Thauvin - Genetics Center, University Hospital of Dijon, University of Burgundy, Dijon, France
Quentin Thomas - Department of Neurology, University Hospital of Dijon, University of Burgundy, Dijon, France
Camille Tisserand - Neurology Department, Hôpital Pierre-Paul Riquet, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
Cédric Turpinat - Service de Neurologie, Hopital Gui de Chauliac, CHU de Montpellier, Montpellier, France
Laurène Van Damme - Service de Neurologie, Centre Hospitalier Perpignan, Perpignan, France
Olivier Vercruysse - Department of Neurology, Saint Brieuc Hospital, Saint-Brieuc, France
Nicolas Villain - Institut du Cerveau
Nathalie Wagemann - CHU Nantes, Memory Center, Inserm CIC4, 44093 Nantes, France
Camille Charbonnier - Inserm
David Wallon - Inserm
Détails de publication: Genetics in medicine, Vol.26(5), p.101082
Éditeur: Elsevier Inc
Identifiants: 99140186709311
Unité académique: Institut des Neurosciences de Montpellier - INM
Langue: English
Type de ressource: Journal article