Overview

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

Findings

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 2945) was a woman who was 53 years old at disease onset. She first experienced memory loss, and at 55 developed disorientation, poor comprehension, and difficulties with planning and organizing. Her deceased mother had dementia with symptoms emerging at age 55. Genetic analysis revealed a ~0.7Mb duplication including two genes: APP and CYYR1. Her APOE genotype was APOE3/4. 

APP duplications are rare or absent from the general population (Sharp et al., 2005). However, they may be a relatively common cause of familial AD in some populations. This may be due to APP being in a recombination hotspot that harbors multiple low copy repeats (Sleegers et al., 2006; Rovelet-Lecrux et al., 2006).

Neuropathology
Neuropathological data are unavailable (Kasuga et al., 2009), but MRI of the proband’s brain showed mild cortical atrophy, although medial temporal areas were relatively spared. Vascular alterations, which are common in carriers of APP duplications, including microhemorrhages and subcortical hyperintensities, were not observed. 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).

Pathogenicity

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.

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References

Paper Citations

1. Kasuga K, Shimohata T, Nishimura A, Shiga A, Mizuguchi T, Tokunaga J, Ohno T, Miyashita A, Kuwano R, Matsumoto N, Onodera O, Nishizawa M, Ikeuchi T. 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. Sharp AJ, Locke DP, McGrath SD, Cheng Z, Bailey JA, Vallente RU, Pertz LM, Clark RA, Schwartz S, Segraves R, Oseroff VV, Albertson DG, Pinkel D, Eichler EE. 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. Sleegers K, Brouwers N, Gijselinck I, Theuns J, Goossens D, Wauters J, Del-Favero J, Cruts M, van Duijn CM, Van Broeckhoven C. 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.
4. Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerrière A, Vital A, Dumanchin C, Feuillette S, Brice A, Vercelletto M, Dubas F, Frebourg T, Campion D. 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