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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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).
The authors declare no conflict of interest.
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Le Guennec, K., Quenez, O., Nicolas, G. et al. 17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression. Mol Psychiatry 22, 1119–1125 (2017). https://doi.org/10.1038/mp.2016.226
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