Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
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 mutation was identified in a screen of patients with early onset Alzheimer’s disease from 28 French hospitals (Lanoiselée et al., 2017). Families were included when at least two first-degree relatives, spanning two generations, suffered from early onset AD with an age of onset of 65 years or younger. Age at onset in this pedigree (EXT 857), which included three affected individuals across two generations, ranged from 50 to 62 years (Grangeon et al., 2023).

A ~1.5Mb duplication harboring eight genes from MRPL39 to ADAMTS5, including APP, was identified in the proband and an affected sister 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. This individual had an APOE3/E4 genotype.

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
Neuropathological data are unavailable, but cerebrospinal fluid biomarkers, including Aβ42, tau and phospho-tau 181, in the proband were consistent with AD pathology (Lanoiselée et al., 2017). Brain MRI of the proband showed no signs of cerebral amyloid angiopathy—a condition often associated with APP duplications—and no intracerebral hemorrhages, microbleeds, nor cortical superficial siderosis (Grangeon et al., 2023).

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.

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References

News Citations

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

Paper Citations

1. Lanoiselée HM, Nicolas G, Wallon D, Rovelet-Lecrux A, Lacour M, Rousseau S, Richard AC, Pasquier F, Rollin-Sillaire A, Martinaud O, Quillard-Muraine M, de la Sayette V, Boutoleau-Bretonniere C, Etcharry-Bouyx F, Chauviré V, Sarazin M, le Ber I, Epelbaum S, Jonveaux T, Rouaud O, Ceccaldi M, Félician O, Godefroy O, Formaglio M, Croisile B, Auriacombe S, Chamard L, Vincent JL, Sauvée M, Marelli-Tosi C, Gabelle A, Ozsancak C, Pariente J, Paquet C, Hannequin D, Campion D, collaborators of the CNR-MAJ project. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.
2. Grangeon L, Charbonnier C, Zarea A, Rousseau S, Rovelet-Lecrux A, Bendetowicz D, Lemaitre M, Malrain C, Quillard-Muraine M, Cassinari K, Maltete D, Pariente J, Moreaud O, Magnin E, Cretin B, Mackowiak MA, Sillaire AR, Vercelletto M, Dionet E, Felician O, Rod-Olivieri P, Thomas-Antérion C, Godeneche G, Sauvée M, Cartz-Piver L, Le Ber I, Chauvire V, Jonveaux T, Balageas AC, Laquerriere A, Duyckaerts C, Vital A, de Paula AM, Meyronet D, Guyant-Marechal L, Hannequin D, Tournier-Lasserve E, Campion D, CNR-MAJ collaborators, Nicolas G, Wallon D. Phenotype and imaging features associated with APP duplications. Alzheimers Res Ther. 2023 May 11;15(1):93. PubMed.
3. 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.
4. 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.
5. 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.
6. 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.
7. Lott IT, Head E. Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat Rev Neurol. 2019 Mar;15(3):135-147. PubMed.
8. 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.
9. 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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