Mutations

APP Duplication EXT-019 [LINC00158-USP16]

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Cerebral Amyloid Angiopathy
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy
Reference Assembly: GRCh37/hg19
dbSNP ID: NA
Coding/Non-Coding: Both
DNA Change: Duplication
Expected RNA Consequence: Duplication
Expected Protein Consequence: Duplication
Genomic Region: Chromosome 21

Findings

This APP duplication was reported in a study of 24 French families carrying APP duplications (Grangeon et al., 2023). Duplications were detected by analyzing the APP locus on chromosome 21 using quantitative multiplex PCR of short fluorescent fragments (QMPSF)—a method that simultaneously amplifies multiple short genomic sequences—or digital droplet PCR.

The family (EXT_019) had five affected members, with ages at onset ranging from 42 to 59 years and disease duration of 12 years. Genetic analysis of the proband and his mother revealed a ~3.6Mb duplication with 11 genes between LINC00158 and USP16, including APP. Before their deaths, both carriers had developed dementia. The mother also had lobar hemorrhage and seizures. Three deceased, non-genotyped family members were also affected, including the proband’s maternal grandfather and an aunt who developed dementia at ages 49 and 59, respectively, and another maternal aunt with lobar hemorrhage at age 53. 

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).

Neuropathology
One carrier had neuropathology consistent with AD and cerebral amyloid angiopathy (CAA) (Grangeon et al., 2023). Diffuse cerebral atrophy, particularly in the temporo-parietal region resulting in ventricular dilation, was observed. Neuronal loss was evident in the cortex and brainstem. CAA was diffuse and severe, including thickening of leptomeningeal and parenchymal blood vessels. Meningeal vessel deposits were nearly always positive for Aβ40, while amyloid plaques in the hippocampus and parahippocampal gyrus were positive for Aβ42.

Biological Effect
The biological effect of this specific APP duplication is unknown, but a study of multiple carriers of APP duplications showed that, as expected, the median levels of APP mRNA in blood were approximately 1.4-fold higher in carriers compared with non-carriers (Pottier et al., 2012). However, variability between duplications and individual carriers suggests other factors, such as the specific genes included in the duplication, may modulate expression (e.g., Lott and Head, 2019).

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).

Pathogenicity

Alzheimer's Disease : Pathogenic

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

PS1-M

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Duplication EXT-019 [LINC00158-USP16]: Similar to other APP duplications known to be pathogenic, although exact DNA changes varied.

PS3-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Duplication EXT-019 [LINC00158-USP16]: Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP dosage.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

PM2-M

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: 14 Jul 2023

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References

News Citations

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

Paper Citations

  1. . Phenotype and imaging features associated with APP duplications. Alzheimers Res Ther. 2023 May 11;15(1):93. 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. . Amyloid-β protein precursor gene expression in alzheimer's disease and other conditions. J Alzheimers Dis. 2012;28(3):561-6. PubMed.
  6. . Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat Rev Neurol. 2019 Mar;15(3):135-147. PubMed.
  7. . 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.
  8. . 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. . Phenotype and imaging features associated with APP duplications. Alzheimers Res Ther. 2023 May 11;15(1):93. PubMed.

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