APP Duplication PED 3281 [LINC00158-ADAMTS5]

Other Names: PED 3281 [C21orf42-ADAMTS5]


Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2
Clinical Phenotype: Alzheimer's Disease
Coding/Non-Coding: Both
DNA Change: Duplication
Expected RNA Consequence: Duplication
Expected Protein Consequence: Duplication
Genomic Region: Chromosome 21


This APP duplication was identified in a cohort of Japanese patients with familial and early onset sporadic Alzheimer’s disease (AD) (Kasuga et al., 2009). Duplications were detected using microsatellite markers within and flanking the APP locus to amplify genomic DNA using PCR. Duplications were confirmed using a microarray for comparative genomic hybridization analysis.

The proband of this family (PED 3281) was a woman who was 52 years old at disease onset. She experienced cognitive decline including memory loss and impaired visuo-perceptual skills. No signs of Down syndrome were observed. The proband’s father died at age 54 years from hemorrhagic stroke. Her paternal grandfather and a paternal aunt, both deceased, had dementia.

Genetic analysis of the proband revealed a ~4.2Mb duplication with 9 genes spanning LINC00158 to ADAMTS5, including APP. Her APOE genotype was APOE3/3.

APP duplications are rare or absent from the general population (Sharp et al., 2005) and appear to be a rare cause of early onset AD (e.g., Hooli et al., 2012; June 2013 news; Wang et al., 2023).

Neuropathological data are unavailable but MRI of the proband’s brain at age 53 indicated multiple old microbleeds in the subcortical white matter and FLAIR imaging revealed extensive white matter hyperintensities (Kasuga et al., 2009). Cortical atrophy was mild with preservation of the medial temporal areas, including the entorhinal cortex. Cerebrospinal fluid levels of Aβ40, Aβ42, and tau were consistent with AD.

Biological Effect
As expected, quantitative RT-PCR of total RNA from the proband’s peripheral blood revealed a ~1.5-fold increase in APP mRNA relative to controls (Kasuga et al., 2009).

Of note, APP is in a recombination hotspot harboring multiple low copy repeats that may facilitate APP duplication (Sleegers et al., 2006; Rovelet-Lecrux et al., 2006).


Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.


Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Duplication PED 3281 [LINC00158-ADAMTS5]: Similar to other APP duplications known to be pathogenic, although exact DNA changes varied.


Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.


Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. Duplication PED 3281 [LINC00158-ADAMTS5]: Mutation encompasses the APP gene, a mutational hotspot and a gene known to play a well-established functional role in AD.


Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 17 Jul 2023


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News Citations

  1. Do Copy Number Variations Point to Potential AD Genes?

Paper Citations

  1. . Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease. J Neurol Neurosurg Psychiatry. 2009 Sep;80(9):1050-2. PubMed.
  2. . Segmental duplications and copy-number variation in the human genome. Am J Hum Genet. 2005 Jul;77(1):78-88. Epub 2005 May 25 PubMed.
  3. . Role of common and rare APP DNA sequence variants in Alzheimer disease. Neurology. 2012 Apr 17;78(16):1250-7. Epub 2012 Apr 4 PubMed.
  4. . Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer's Diseases Sequencing Project Subjects. 2023 Sep 13 10.1101/2023.09.13.23295505 (version 1) medRxiv.
  5. . APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy. Brain. 2006 Nov;129(Pt 11):2977-83. Epub 2006 Aug 18 PubMed.
  6. . APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2006 Jan;38(1):24-6. Epub 2005 Dec 20 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease. J Neurol Neurosurg Psychiatry. 2009 Sep;80(9):1050-2. PubMed.

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