Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Cerebral Amyloid Angiopathy
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PP1
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 variant, a 250-750 Kb duplication including a single gene, APP, was identified in a Dutch family (1104) spanning four generations with multiple members suffering from early onset Alzheimer’s disease, cerebral amyloid angiopathy, and seizures (Sleegers et al., 2006). Duplications were detected using a quantitative PCR-based method and fluorescence in situ hybridization for verification. 

Four duplication carriers, all siblings of each other, were identified. Three died with probable AD with ages at onset of 47, 53, and 62 years, and deaths at 51, 66 and 64, respectively. All were APOE3 homozygotes. The fourth carrier was alive and unaffected, but they were only 58 years old, within one standard deviation of the family’s mean age at onset. Of note, one sibling who did not carry the duplication was unaffected at the time of their death at 71, and three non-carrier cousins remained unaffected after the age of 64 years. Thus, the duplication segregated with disease. Other factors predisposing the family to neurological disease may have been present, however, since one non-carrier sibling died at 35 with a history of stroke and a non-carrier cousin died at 62 with Lewy body-variant AD. 

Interestingly, an individual from a different Dutch family was found to also carry a similarly sized duplication and have familial AD. Their age at onset was 55 and death occurred at 67. They developed severe rigidity, convulsions, and myoclonus. Their APOE genotype was APOE3/E4. The patient’s mother and maternal uncle were also affected but were not genotyped.  The authors noted a common founder might explain the presence of the duplication in the two families.

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, examination of the brain at autopsy revealed neuropathology consistent with AD and cerebral amyloid angiopathy (Sleegers et al., 2006). In addition, CT brain scans of three carriers showed extensive cortical and subcortical atrophy. Of note, the carrier with convulsions and myoclonus did not have focal lesions.

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, can modulate expression (e.g., Lott and Head, 2019).

The authors noted that this duplication, which harbors a single gene, indicates that increased APP levels appear to be sufficient to cause early onset AD (Sleegers et al., 2006).

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.

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References

News Citations

1. Do Copy Number Variations Point to Potential AD Genes? 27 Jun 2013

Paper Citations

1. 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.
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. Hooli BV, Mohapatra G, Mattheisen M, Parrado AR, Roehr JT, Shen Y, Gusella JF, Moir R, Saunders AJ, Lange C, Tanzi RE, Bertram L. 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. Wang H, Dombroski BA, Cheng P-L, Tucci A, Si Y-q, Farrell JJ, Tzeng J-Y, Leung YY, Malamon JS, Wang L-S, Vardarajan BN, Farrer LA, Schellenberg GD, Lee W-P. 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. Pottier C, Wallon D, Lecrux AR, Maltete D, Bombois S, Jurici S, Frebourg T, Hannequin D, Campion D. Amyloid-β protein precursor gene expression in alzheimer's disease and other conditions. J Alzheimers Dis. 2012;28(3):561-6. PubMed.
6. Lott IT, Head E. Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat Rev Neurol. 2019 Mar;15(3):135-147. PubMed.
7. 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

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