Over 200 rare and fully penetrant pathogenic mutations in amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2) cause a subset of early-onset familial Alzheimer’s disease (EO-FAD). Of these, 21 cases of EO-FAD families carrying unique APP locus duplications remain the only pathogenic copy number variations (CNVs) identified to date in Alzheimer’s disease (AD). Using high-density DNA microarrays, we performed a comprehensive genome-wide analysis for the presence of rare CNVs in 261 EO-FAD and early/mixed-onset pedigrees. Our analysis revealed 10 novel private CNVs in 10 EO-FAD families overlapping a set of genes that includes: A2BP1, ABAT, CDH2, CRMP1, DMRT1, EPHA5, EPHA6, ERMP1, EVC, EVC2, FLJ35024 and VLDLR. In addition, CNVs encompassing two known frontotemporal dementia genes, CHMP2B and MAPT were found. To our knowledge, this is the first study reporting rare gene-rich CNVs in EO-FAD and early/mixed-onset AD that are likely to underlie pathogenicity in familial AD and perhaps related dementias.
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The enhanced association between mutant CHMP2B and spastin is a novel pathological link between frontotemporal dementia and hereditary spastic paraplegias
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Molecular Psychiatry Open Access 07 April 2022
npj Genomic Medicine Open Access 13 August 2021
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This study was funded by grants from the NIMH and the Cure Alzheimer’s Fund.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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Hooli, B., Kovacs-Vajna, Z., Mullin, K. et al. Rare autosomal copy number variations in early-onset familial Alzheimer’s disease. Mol Psychiatry 19, 676–681 (2014). https://doi.org/10.1038/mp.2013.77
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The enhanced association between mutant CHMP2B and spastin is a novel pathological link between frontotemporal dementia and hereditary spastic paraplegias
Acta Neuropathologica Communications (2022)
Molecular Psychiatry (2022)
Human Genomics (2021)
npj Genomic Medicine (2021)
Molecular Neurobiology (2021)