title: 17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression.
abstract: To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case-control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6-1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPT duplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-β deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early-onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series.
authors.affiliation: Inserm, U1079, faculté de médecine, Rouen University, IRIB, Normandy University, Rouen, France.|Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France.
authors.forename: K
authors.initials: K
authors.lastname: Le Guennec
authors.affiliation: Inserm, U1079, faculté de médecine, Rouen University, IRIB, Normandy University, Rouen, France.|Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.
authors.forename: O
authors.initials: O
authors.lastname: Quenez
authors.affiliation: Inserm, U1079, faculté de médecine, Rouen University, IRIB, Normandy University, Rouen, France.|Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.|Department of Genetics, Rouen University Hospital, Rouen, France.
authors.forename: G
authors.initials: G
authors.lastname: Nicolas
authors.affiliation: Inserm, U1079, faculté de médecine, Rouen University, IRIB, Normandy University, Rouen, France.|Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.|Department of Neurology, Rouen University Hospital, Rouen, France.
authors.forename: D
authors.initials: D
authors.lastname: Wallon
authors.affiliation: Inserm, U1079, faculté de médecine, Rouen University, IRIB, Normandy University, Rouen, France.|Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.
authors.forename: S
authors.initials: S
authors.lastname: Rousseau
authors.affiliation: Inserm, U1079, faculté de médecine, Rouen University, IRIB, Normandy University, Rouen, France.|Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.
authors.forename: A-C
authors.initials: AC
authors.lastname: Richard
authors.affiliation: Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupoli, Greece.
authors.forename: J
authors.initials: J
authors.lastname: Alexander
authors.affiliation: Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupoli, Greece.
authors.forename: P
authors.initials: P
authors.lastname: Paschou
authors.affiliation: Inserm, U1079, faculté de médecine, Rouen University, IRIB, Normandy University, Rouen, France.|Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.
authors.forename: C
authors.initials: C
authors.lastname: Charbonnier
authors.affiliation: Inserm, U1167, Lille, France.|Institut Pasteur de Lille, Lille, France.|Université Lille-Nord de France, Lille, France.
authors.forename: C
authors.initials: C
authors.lastname: Bellenguez
authors.affiliation: Inserm, U1167, Lille, France.|Institut Pasteur de Lille, Lille, France.|Université Lille-Nord de France, Lille, France.
authors.forename: B
authors.initials: B
authors.lastname: Grenier-Boley
authors.affiliation: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors.forename: D
authors.initials: D
authors.lastname: Lechner
authors.affiliation: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors.forename: M-T
authors.initials: MT
authors.lastname: Bihoreau
authors.affiliation: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors.forename: R
authors.initials: R
authors.lastname: Olaso
authors.affiliation: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors.forename: A
authors.initials: A
authors.lastname: Boland
authors.affiliation: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors.forename: V
authors.initials: V
authors.lastname: Meyer
authors.affiliation: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.|Fondation Jean Dausset, Centre d'études du Polymorphisme Humain, Paris, France.
authors.forename: J-F
authors.initials: JF
authors.lastname: Deleuze
authors.affiliation: Inserm, U1167, Lille, France.|Institut Pasteur de Lille, Lille, France.|Université Lille-Nord de France, Lille, France.
authors.forename: P
authors.identifier: 0000-0001-9088-234X
authors.initials: P
authors.lastname: Amouyel
authors.affiliation: McGill University and Génome Québec Innovation Centre, Montréal, QC, Canada.
authors.forename: H M
authors.initials: HM
authors.lastname: Munter
authors.affiliation: McGill University and Génome Québec Innovation Centre, Montréal, QC, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Bourque
authors.affiliation: McGill University and Génome Québec Innovation Centre, Montréal, QC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: Inserm, U1079, faculté de médecine, Rouen University, IRIB, Normandy University, Rouen, France.|Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France.|Department of Genetics, Rouen University Hospital, Rouen, France.
authors.forename: T
authors.initials: T
authors.lastname: Frebourg
authors.affiliation: Inserm, UMR 1087, l'institut du thorax, CHU Nantes, Nantes, France.|CNRS, UMR 6291, Université de Nantes, Nantes, France.
authors.forename: R
authors.initials: R
authors.lastname: Redon
authors.affiliation: INSERM, U1219, Bordeaux, France.|Université de Bordeaux, Bordeaux, France.
authors.forename: L
authors.identifier: 0000-0002-3274-937X
authors.initials: L
authors.lastname: Letenneur
authors.affiliation: INSERM, U1219, Bordeaux, France.|Université de Bordeaux, Bordeaux, France.
authors.forename: J-F
authors.initials: JF
authors.lastname: Dartigues
authors.affiliation: CNR-MAJ, Rouen University Hospital, Rouen, France.|Department of Neurology, Rouen University Hospital, Rouen, France.
authors.forename: O
authors.initials: O
authors.lastname: Martinaud
authors.affiliation: Institute of Pathology and Neuropathology, Kepler University Hospital, Linz, Austria.
authors.forename: O
authors.initials: O
authors.lastname: Kalev
authors.affiliation: Department of Neurology, Alexandrovska University Hospital, Medical University-Sofia, Sofia, Bulgaria.
authors.forename: S
authors.initials: S
authors.lastname: Mehrabian
authors.affiliation: Department of Neurology, Alexandrovska University Hospital, Medical University-Sofia, Sofia, Bulgaria.
authors.forename: L
authors.initials: L
authors.lastname: Traykov
authors.affiliation: Institute of Neurology, Medical University Vienna, Vienna, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Ströbel
authors.affiliation: Sorbonne Universités, Inserm, CNRS, UPMC Univ Paris 06, UMR S 1127, Paris, France.|CNR-MAJ, IMMA, département des maladies du système nerveux, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: Le Ber
authors.affiliation: Sorbonne Universités, Inserm, CNRS, UPMC Univ Paris 06, UMR S 1127, Paris, France.|CNR-MAJ, IMMA, département des maladies du système nerveux, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Caroppo
authors.affiliation: Sorbonne Universités, Inserm, CNRS, UPMC Univ Paris 06, UMR S 1127, Paris, France.|CNR-MAJ, IMMA, département des maladies du système nerveux, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Epelbaum
authors.affiliation: Centre Mémoire de Ressources et de Recherche de Lorraine, CHRU Nancy Service de Gériatrie, Hôpital de Brabois, Vandoeuvre les Nancy, France.|Laboratoire INTERPSY, EA 4432, Groupe de recherche sur les Communications (GRC), Université de Lorraine, Psychologie, Nancy, France.
authors.forename: T
authors.initials: T
authors.lastname: Jonveaux
authors.affiliation: CNR-MAJ Inserm U1171, Univ Lille, CHU, Lille, France.
authors.forename: F
authors.initials: F
authors.lastname: Pasquier
authors.affiliation: CNR-MAJ Inserm U1171, Univ Lille, CHU, Lille, France.
authors.forename: A
authors.initials: A
authors.lastname: Rollin-Sillaire
authors.affiliation: Inserm, UMR1078, CHU Brest, Université Bretagne Occidentale, Brest, France.
authors.forename: E
authors.initials: E
authors.lastname: Génin
authors.affiliation: Department of Neurology, Rouen University Hospital, Rouen, France.|Department of Neurophysiology, Rouen University Hospital, Rouen, France.
authors.forename: L
authors.initials: L
authors.lastname: Guyant-Maréchal
authors.affiliation: Institute of Neurology, Medical University Vienna, Vienna, Austria.
authors.forename: G G
authors.initials: GG
authors.lastname: Kovacs
authors.affiliation: Inserm, U1167, Lille, France.|Institut Pasteur de Lille, Lille, France.|Université Lille-Nord de France, Lille, France.
authors.forename: J-C
authors.initials: JC
authors.lastname: Lambert
authors.affiliation: Inserm, U1079, faculté de médecine, Rouen University, IRIB, Normandy University, Rouen, France.|Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.|Department of Genetics, Rouen University Hospital, Rouen, France.|Department of Neurology, Rouen University Hospital, Rouen, France.
authors.forename: D
authors.initials: D
authors.lastname: Hannequin
authors.affiliation: Inserm, U1079, faculté de médecine, Rouen University, IRIB, Normandy University, Rouen, France.|Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.|Department of Research, Rouvray Psychiatric Hospital, Sotteville-lès-Rouen, France.
authors.forename: D
authors.initials: D
authors.lastname: Campion
authors.affiliation: Inserm, U1079, faculté de médecine, Rouen University, IRIB, Normandy University, Rouen, France.|Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.
authors.forename: A
authors.initials: A
authors.lastname: Rovelet-Lecrux
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D003704:Dementia / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D020440:Gene Duplication / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000473:pathology; D059906:Neuroimaging; D024801:Tauopathies / Q000235:genetics; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins