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.

Protein astrogliopathies in human neurodegenerative diseases and aging

“…These resemble GFA of gray matter ARTAG supporting the concept that some of these might be pre‐mature forms of astrocytic tau pathologies . Interestingly, further ARTAG types (subpial TSA), together with cortical astrocytic plaques, have been observed in a 49‐year‐old demented individual with MAPT gene duplication . This case indicates that an imbalance of tau homeostasis contributes to the development of a clearly age‐related pathology as observed earlier with mutations that alter the 3R:4R tau isoform ratio .…”

Genome‐wide survey of copy number variants finds MAPT duplications in progressive supranuclear palsy

“…Taken together with a copious body of evidence connecting MAPT with PSP genetically and neuropathologically, this finding suggests that duplication of MAPT is a significant although relatively uncommon cause of PSP. Duplications spanning the MAPT gene have been previously reported in 12 patients, including in children with mild learning difficulties, developmental delay, and variable dysmorphic features; a patient with a presumed familial frontotemporal dementia phenotype; 3 siblings with early‐onset Alzheimer's disease; and 5 additional patients with Alzheimer's‐like cognitive impairment . In most cases, the extent of the causal CNV is not clearly defined.…”

“…Duplications spanning the MAPT gene have been previously reported in 12 patients, including in children with mild learning difficulties, developmental delay, and variable dysmorphic features 31 ; a patient with a presumed familial frontotemporal dementia phenotype 32 ; 3 siblings with early-onset Alzheimer's disease 33 ; and 5 additional patients with Alzheimer's-like cognitive impairment. 34 In most cases, the extent of the causal CNV is not clearly defined. In the cases with Alzheimer's disease, the CNV appeared to span the MAPT gene 33 and possibly include the CRHR1 and KANSL1 genes, 34 as in our case, suggesting that the clinical phenotype of MAPT duplications may have variable expressivity.…”

“…34 In most cases, the extent of the causal CNV is not clearly defined. In the cases with Alzheimer's disease, the CNV appeared to span the MAPT gene 33 and possibly include the CRHR1 and KANSL1 genes, 34 as in our case, suggesting that the clinical phenotype of MAPT duplications may have variable expressivity.…”

GenPipes: an open-source framework for distributed and scalable genomic analyses

“…GenPipes is also being redeveloped to use the Common Workflow Language (CWL) to provide a cloud compatible version more seamlessly and more Scheduler objects, like DRMAA, are being added to expand compatibility with more platforms. GenPipes has become a reliable bioinformatics solution that has been used in various genomics publications for DNA-Seq[60][61][62][63][64][65][66][67], RNA-Seq[68] and ChIP-Seq[69] analyses. GenPipes is currently available as source code, as well as a Docker image for easy installation and use.…”