Mutations

APP Duplication EXT-298 [GABPA-CYYR1]

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
Coding/Non-Coding: Both
DNA Change: Duplication
Expected RNA Consequence: Duplication
Expected Protein Consequence: Duplication
Genomic Region: Chromosome 21

Findings

This APP duplication was found in a large French study reporting seven families with APP duplications and autosomal-dominant, early onset Alzheimer's disease. All probands met NINCDS-ADRDA criteria for probable AD and had a family history of disease (Wallon et al., 2012). 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.

The proband’s family (EXT 298) included three affected individuals with ages at onset ranging from 46 to 53 years, and disease duration ranging from six to 13 years (Wallon et al., 2012, Grangeon et al., 2023). Genetic analysis was performed only on the proband who carried a ~0.8Mb APP duplication spanning three genes: GABPA, APP, and CYYR1. He had an APOE3/E4 genotype. His symptoms started at age 46 and included dementia and seizures. His deceased father developed dementia at age 50. 

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
In one carrier, neuropathology was consistent with AD and severe cerebral amyloid angiopathy (CAA) (Grangeon et al., 2023). Moreover, MRI data from the proband revealed probable CAA with 56 cerebral microbleeds.

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-298 [GABPA-CYYR1]: 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-298 [GABPA-CYYR1]: 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. Duplication EXT-298 [GABPA-CYYR1]: Mutation encompasses the APP gene, a mutational hotspot and a gene known to play a well-established functional role in AD.

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: 12 Jul 2023

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References

News Citations

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

Paper Citations

  1. . The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012 Jan 1;30(4):847-56. PubMed.
  2. . Phenotype and imaging features associated with APP duplications. Alzheimers Res Ther. 2023 May 11;15(1):93. PubMed.
  3. . 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.
  4. . 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.
  5. . 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.
  6. . Amyloid-β protein precursor gene expression in alzheimer's disease and other conditions. J Alzheimers Dis. 2012;28(3):561-6. PubMed.
  7. . Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat Rev Neurol. 2019 Mar;15(3):135-147. PubMed.
  8. . 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.
  9. . 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. . The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012 Jan 1;30(4):847-56. PubMed.

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