Assessment of Mendelian and risk-factor genes in Alzheimer disease: A prospective nationwide clinical utility study and recommendations for genetic screening
Genetics in Medicine. 2024-05-01; 26(5): 101082
DOI: 10.1016/j.gim.2024.101082
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Nicolas G(1), Zaréa A(2), Lacour M(2), Quenez O(3), Rousseau S(3), Richard
AC(3), Bonnevalle A(4), Schramm C(3), Olaso R(5), Sandron F(5), Boland A(5),
Deleuze JF(5), Andriuta D(6), Anthony P(7), Auriacombe S(8), Balageas AC(9),
Ballan G(10), Barbay M(6), Béjot Y(11), Belliard S(12), Benaiteau M(13), Bennys
K(14), Bombois S(15), Boutoleau-Bretonnière C(16), Branger P(17), Carlier J(13),
Cartz-Piver L(18), Cassagnaud P(19), Ceccaldi MP(20), Chauviré V(21), Chen
Y(22), Cogez J(17), Cognat E(23), Contegal-Callier F(24), Corneille L(20),
Couratier P(25), Cretin B(26), Crinquette C(19), Dauriat B(27), Dautricourt
S(28), de la Sayette V(29), de Liège A(30), Deffond D(31), Demurger F(32),
Deramecourt V(22), Derollez C(19), Dionet E(31), Doco Fenzy M(33), Dumurgier
J(23), Dutray A(34), Etcharry-Bouyx F(21), Formaglio M(28), Gabelle A(14),
Gainche-Salmon A(35), Godefroy O(6), Graber M(36), Gregoire C(37), Grimaldi
S(20), Gueniat J(36), Gueriot C(20), Guillet-Pichon V(21), Haffen S(38), Hanta
CR(35), Hardy C(2), Hautecloque G(7), Heitz C(39), Hourregue C(40), Jonveaux
T(41), Jurici S(42), Koric L(43), Krolak-Salmon P(28), Lagarde J(44), Lanoiselée
HM(45), Laurens B(37), Le Ber I(15), Le Guyader G(46), Leblanc A(47), Lebouvier
T(22), Levy R(15), Lippi A(48), Mackowiak MA(19), Magnin E(49), Marelli C(48),
Martinaud O(29), Maureille A(19), Migliaccio R(15), Milongo-Rigal E(13), Mohr
S(36), Mollion H(28), Morin A(50), Nivelle J(51), Noiray C(44), Olivieri P(44),
Paquet C(23), Pariente J(52), Pasquier F(22), Perron A(7), Philippi N(26),
Planche V(53), Pouclet-Courtemanche H(54), Rafiq M(52), Rollin-Sillaire A(19),
Roué-Jagot C(44), Saracino D(15), Sarazin M(44), Sauvée M(55), Sellal F(56),
Teichmann M(57), Thauvin C(58), Thomas Q(59), Tisserand C(13), Turpinat C(48),
Van Damme L(34), Vercruysse O(60), Villain N(15), Wagemann N(16), Charbonnier
C(61), Wallon D(2).
Author information:
(1)Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Department
of Genetics and CNRMAJ, F-76000 Rouen, France. Electronic address:
.
(2)Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Department
of Neurology and CNRMAJ, F-76000 Rouen, France.
(3)Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Department
of Genetics and CNRMAJ, F-76000 Rouen, France.
(4)Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Department
of Genetics and CNRMAJ, F-76000 Rouen, France; Univ Rouen Normandie, Normandie
Univ, Inserm U1245 and CHU Rouen, Department of Neurology and CNRMAJ, F-76000
Rouen, France.
(5)Université Paris-Saclay, CEA, Centre National de Recherche en Génomique
Humaine (CNRGH), Evry, France.
(6)Service de Neurologie CHU Amiens et Laboratoire de Neurosciences
Fonctionnelles et Pathologies, Université de Picardie Jules Verne, Amiens,
France.
(7)Department of Neurology, Hôpitaux Civils de Colmar, F-68000 Colmar, France.
(8)Univ. Bordeaux, CNRS UMR 5293, Institut des Maladies Neurodégénératives,
Bordeaux, France.
(9)Centre Mémoire Ressources et Recherche, CHRU de Tours, Tours, France.
(10)Centre Hospitalier de la Côte Basque, Bayonne, France.
(11)Department of Neurology, University Hospital of Dijon, University of
Burgundy, Dijon, France.
(12)Unité de recherche 1077 INSERM-EPHE-UNICAEN Neuropsychologie & Imagerie de
la Mémoire Humaine (NIMH), Caen, France; Centre Mémoire Ressources et Recherche
Haute Bretagne, CHU Rennes, Rennes, France.
(13)Neurology Department, Hôpital Pierre-Paul Riquet, Centre Hospitalier
Universitaire de Toulouse, Toulouse, France.
(14)Memory Ressources Research Center, Department of Neurology, University
Hospital of Montpellier, Montpellier, France.
(15)Sorbonne Université, INSERM U1127, CNRS 7235, Institut du Cerveau – ICM,
Paris, France; AP-HP Sorbonne Université, Pitié-Salpêtrière Hospital, Department
of Neurology, Institute of Memory and Alzheimer’s Disease, Paris, France.
(16)CHU Nantes, Memory Center, Inserm CIC4, 44093 Nantes, France.
(17)Department of Neurology, Caen University Hospital, Caen, France.
(18)Memory Ressources Research Center, Department of Neurology, University
Hospital of Limoges, France Inserm U1094, IRD U270, EPIMACT, Université of
Limoges, Limoges, France.
(19)CHU Lille, Memory Center, CNRMAJ 59000 Lille, France.
(20)Institute of Neurophysiopathology UMR 7051 Aix Marseille Université &
Assistance Publique de Marseille, Marseille, France.
(21)CMRR, CRMR Neurogénétique, Service de Neurologie, CHU d’ANGERS, Angers,
France.
(22)Univ Lille, CHU Lille, Inserm 1172, Memory center, CNRMAJ, LiCEND, Labex
DistAlz 59000 Lille, France.
(23)Cognitive Neurology Center, AP-HP.Nord, Site Lariboisière Fernand-Widal,
Paris, France; Université Paris Cité, UMR-S 1144, INSERM, Paris, France.
(24)Hospices Civils de Beaune, Consultation mémoire, Beaune, France.
(25)CMRR Limoges, Service de Neurologie CHU Limoges, Limoges, France.
(26)CMRR d’Alsace, Service de Neurologie, CHU Strasbourg, Strasbourg, France.
(27)Service de Génétique Médicale, Hopital Mère-Enfant, CHU Limoges, Limoges,
France.
(28)CMRR Lyon, Department of Neurology, University Hospital of Lyon, Hospices
Civils de Lyon, Lyon, France.
(29)Department of Neurology, Caen University Hospital, Caen, France; Normandie
UNIV, UNICAEN, PSL Research University, EPHE, INSERM, CHU de Caen,
Neuropsychologie et Imagerie de la Mémoire Humaine, Caen, France.
(30)Service de Neurologie, APHP, Hôpital Avicenne, Université Sorbonne Paris
Nord, Bobigny, France.
(31)CMRR Clermont-Ferrand, Service de Neurologie, CHU Clermont-Ferrand,
Clermont-Ferrand, France.
(32)Service de génétique, CHBA, Vannes, France.
(33)Nantes Université, CHU Nantes, CNRS, INSERM, l’institut du thorax, Nantes,
France; CHU Nantes, Service de Génétique, Nantes, France; CHU Reims, Service de
Génétique, Reims, France.
(34)Service de Neurologie, Centre Hospitalier Perpignan, Perpignan, France.
(35)Centre Mémoire Ressources et Recherche Haute Bretagne, CHU Rennes, Rennes,
France.
(36)Centre mémoire ressources et recherche, CHU Dijon, Dijon, France.
(37)CHU de Bordeaux, Pôle de Neurosciences Cliniques, Centre Mémoire de
Ressources et de Recherche, Bordeaux, France.
(38)Centre mémoire Recherche Ressources, Service de Neurologie, CHU Besançon,
Besançon, France.
(39)Institut du cerveau Trocadero, Paris, France; Neurology Department, Hôpital
Universitaire de Nîmes, Nîmes, France.
(40)Cognitive Neurology Center, AP-HP.Nord, Site Lariboisière Fernand-Widal,
Paris, France.
(41)Centre Mémoire de Ressources et de Recherche de Lorraine Service de
Neurologie CHRU Nancy, Nancy, France; Laboratoire 2LPN EA 7489 Université de
Lorraine, Nancy, France.
(42)Consultation Mémoire, Service de Gériatrie, Centre Hospitalier Perpignan,
Perpignan, France.
(43)Institute of Neurophysiopathology UMR 7051 Aix Marseille Université &
Assistance Publique de Marseille, Marseille, France; Aix-Marseille Univ, UMR
7249, CNRS, Centrale Marseille, Institut Fresnel, Marseille, France.
(44)Department of Neurology of Memory and Language, GHU Paris Psychiatrie &
Neurosciences, Hôpital Sainte Anne, F-75014, Paris, France; Université
Paris-Cité, F-75006 Paris, France; Université Paris-Saclay, BioMaps, Service
Hospitalier Frédéric Joliot CEA, CNRS, Inserm, F-91401, Orsay, France.
(45)Service de neurologie, Centre Hospitalier Régional d’Orléans, Orléans,
France.
(46)Service de Génétique, CHU Poitiers, 86022 Poitiers Cedex, France.
(47)Consultations neurologiques, HIA Clermont-Tonnerre, Brest, France; Service
de neurologie, CHU Cavale-Blanche, Brest, France.
(48)Service de Neurologie, Hopital Gui de Chauliac, CHU de Montpellier,
Montpellier, France.
(49)Laboratoire de neuroscience, Université de Franche-Comté UFC et Service de
Neurologie, CMRR, CHU Besançon, Besançon, France.
(50)Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Department
of Neurology and CNRMAJ, F-76000 Rouen, France; Département de Psychiatrie,
Centre Hospitalier du Rouvray, Université de Rouen, 76000, Sotteville-lès-Rouen,
France.
(51)CH Ales Cévennes, Alès, France.
(52)Neurology Department, Hôpital Pierre-Paul Riquet, Centre Hospitalier
Universitaire de Toulouse, Toulouse, France; Toulouse NeuroImaging Center
(ToNIC), INSERM-University of Toulouse Paul Sabatier, Toulouse, France.
(53)Univ. Bordeaux, CNRS UMR 5293, Institut des Maladies Neurodégénératives,
Bordeaux, France; CHU de Bordeaux, Pôle de Neurosciences Cliniques, Centre
Mémoire de Ressources et de Recherche, Bordeaux, France.
(54)Department of Neurology, CHU Nantes, Nantes, France.
(55)Centre Mémoire de Ressources et de Recherche, Pôle PReNeLe, CHU Grenoble
Alpes CS 10226, 38043 Grenoble Cedex 9, France; Unité de recherche mixte
Université Grenoble Alpes/Université Savoie Montblanc, CNRS UMR 5115,
Laboratoire de Psychologie et Neurocognition (LPNC), 38000 Grenoble, France.
(56)Department of Neurology, Hôpitaux Civils de Colmar, F-68000 Colmar, France;
University of Strasbourg, Medicine Faculty, INSERM, U-1118, Strasbourg, France.
(57)AP-HP Sorbonne Université, Pitié-Salpêtrière Hospital, Department of
Neurology, Institute of Memory and Alzheimer’s Disease, Paris, France.
(58)Genetics Center, University Hospital of Dijon, University of Burgundy,
Dijon, France.
(59)Department of Neurology, University Hospital of Dijon, University of
Burgundy, Dijon, France; Genetics Center, University Hospital of Dijon,
University of Burgundy, Dijon, France.
(60)Department of Neurology, Saint Brieuc Hospital, Saint-Brieuc, France.
(61)Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Department of
Biostatistics and CNRMAJ, F-76000 Rouen, France.
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.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.gim.2024.101082
PMID: 38281098
Conflict of interest statement: Conflict of Interest The authors have no
conflict of interest to declare.