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.

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Acknowledgements

This study was funded by grants from the Clinical Research Hospital Program from the French Ministry of Health (GMAJ, PHRC 2008/067), the CNR-MAJ and the JPND PERADES (ANR-13-JPRF-0001-04). This work was supported by France Génomique, Labex GENMED ANR-10-LABX-0013, the National Foundation for Alzheimer’s disease and related disorders, the Institut Pasteur de Lille, the Centre National de Génotypage, Inserm, FRC (fondation pour la recherche sur le cerveau) and by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer’s disease). We are indebted to the Banque d'ADN et de cellules-Institut du Cerveau et de la Moelle épinière (ICM-Inserm U1127-UPMC P6 UMR-S 1127-CNRS UMR 7225).

Author information

Author notes

    • K Le Guennec
    •  & O Quenez

    These authors contributed equally to this work.

Affiliations

  1. Inserm, U1079, faculté de médecine, Rouen University, IRIB, Normandy University, Rouen, France

    • K Le Guennec
    • , O Quenez
    • , G Nicolas
    • , D Wallon
    • , S Rousseau
    • , A-C Richard
    • , C Charbonnier
    • , T Frebourg
    • , D Hannequin
    • , D Campion
    •  & A Rovelet-Lecrux
  2. Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France

    • K Le Guennec
    • , O Quenez
    • , G Nicolas
    • , D Wallon
    • , S Rousseau
    • , A-C Richard
    • , C Charbonnier
    • , T Frebourg
    • , D Hannequin
    • , D Campion
    •  & A Rovelet-Lecrux
  3. CNR-MAJ, Rouen University Hospital, Rouen, France

    • O Quenez
    • , G Nicolas
    • , D Wallon
    • , S Rousseau
    • , A-C Richard
    • , C Charbonnier
    • , O Martinaud
    • , D Hannequin
    • , D Campion
    •  & A Rovelet-Lecrux
  4. Department of Genetics, Rouen University Hospital, Rouen, France

    • G Nicolas
    • , T Frebourg
    •  & D Hannequin
  5. Department of Neurology, Rouen University Hospital, Rouen, France

    • D Wallon
    • , O Martinaud
    • , L Guyant-Maréchal
    •  & D Hannequin
  6. Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupoli, Greece

    • J Alexander
    •  & P Paschou
  7. Inserm, U1167, Lille, France

    • C Bellenguez
    • , B Grenier-Boley
    • , P Amouyel
    •  & J-C Lambert
  8. Institut Pasteur de Lille, Lille, France

    • C Bellenguez
    • , B Grenier-Boley
    • , P Amouyel
    •  & J-C Lambert
  9. Université Lille-Nord de France, Lille, France

    • C Bellenguez
    • , B Grenier-Boley
    • , P Amouyel
    •  & J-C Lambert
  10. Centre National de Génotypage, Institut de Génomique, CEA, Evry, France

    • D Lechner
    • , M-T Bihoreau
    • , R Olaso
    • , A Boland
    • , V Meyer
    •  & J-F Deleuze
  11. Fondation Jean Dausset, Centre d’études du Polymorphisme Humain, Paris, France

    • J-F Deleuze
  12. McGill University and Génome Québec Innovation Centre, Montréal, QC, Canada

    • H M Munter
    • , G Bourque
    •  & M Lathrop
  13. Inserm, UMR 1087, l'institut du thorax, CHU Nantes, Nantes, France

    • R Redon
  14. CNRS, UMR 6291, Université de Nantes, Nantes, France

    • R Redon
  15. INSERM, U1219, Bordeaux, France

    • L Letenneur
    •  & J-F Dartigues
  16. Université de Bordeaux, Bordeaux, France

    • L Letenneur
    •  & J-F Dartigues
  17. Institute of Pathology and Neuropathology, Kepler University Hospital, Linz, Austria

    • O Kalev
  18. Department of Neurology, Alexandrovska University Hospital, Medical University-Sofia, Sofia, Bulgaria

    • S Mehrabian
    •  & L Traykov
  19. Institute of Neurology, Medical University Vienna, Vienna, Austria

    • T Ströbel
    •  & G G Kovacs
  20. Sorbonne Universités, Inserm, CNRS, UPMC Univ Paris 06, UMR S 1127, Paris, France

    • I Le Ber
    • , P Caroppo
    •  & S Epelbaum
  21. CNR-MAJ, IMMA, département des maladies du système nerveux, Hôpital Pitié-Salpêtrière, Paris, France

    • I Le Ber
    • , P Caroppo
    •  & S Epelbaum
  22. Centre Mémoire de Ressources et de Recherche de Lorraine, CHRU Nancy Service de Gériatrie, Hôpital de Brabois, Vandoeuvre les Nancy, France

    • T Jonveaux
  23. Laboratoire INTERPSY, EA 4432, Groupe de recherche sur les Communications (GRC), Université de Lorraine, Psychologie, Nancy, France

    • T Jonveaux
  24. CNR-MAJ Inserm U1171, Univ Lille, CHU, Lille, France

    • F Pasquier
    •  & A Rollin-Sillaire
  25. Inserm, UMR1078, CHU Brest, Université Bretagne Occidentale, Brest, France

    • E Génin
  26. Department of Neurophysiology, Rouen University Hospital, Rouen, France

    • L Guyant-Maréchal
  27. Department of Research, Rouvray Psychiatric Hospital, Sotteville-lès-Rouen, France

    • D Campion

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Competing interests

The authors declare no conflict of interest.

Corresponding authors

Correspondence to D Campion or A Rovelet-Lecrux.

Supplementary information

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DOI

https://doi.org/10.1038/mp.2016.226

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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