Mutations
APP Duplication EXT-144 [BTG3-EIF4A1P]
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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 144) included four affected individuals (Wallon et al., 2012, Grangeon et al., 2023). Age at onset was between 42 and 64 years, and disease duration between one and four years. Genetic analysis of the proband and his brother revealed a ~9.7Mb duplication, including APP plus 14 genes spanning BTG3 to EIF4A1P. Both carried an APOE2 allele and both developed lobar hemorrhage and seizures, but only the brother, who had a later age of onset (63 versus 42) had dementia. Their non-genotyped father, who was deceased and began symptoms at age 52, also had lobar hemorrhage and seizures, and a deceased non-genotyped brother, had lobar hemorrhage with onset at age 48. The mutation was reported as segregating with disease, but the authors did not report the identification of unaffected, aged non-carriers (Wallon et al., 2012).
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
The proband had diffuse cerebral atrophy, particularly in the temporo-parietal region resulting in ventricular dilation. Neuronal loss was evident in the cortex and brainstem. Moreover, cerebral amyloid angiopathy (CAA) was diffuse and severe, with a recent hemorrhage found in the pes pedunculi (Grangeon et al., 2023). However, no neurofibrillary tangles were observed. Brain MRI revealed probable CAA in the proband's brother with three intracerebral hemorrhages and 422 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-144 [BTG3-EIF4A1P]: 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-144 [BTG3-EIF4A1P]: 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-144 [BTG3-EIF4A1P]: 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
References
News Citations
Paper Citations
- Wallon D, Rousseau S, Rovelet-Lecrux A, Quillard-Muraine M, Guyant-Maréchal L, Martinaud O, Pariente J, Puel M, Rollin-Sillaire A, Pasquier F, Le Ber I, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Thomas-Antérion C, Paquet C, Moreaud O, Gabelle A, Sellal F, Sauvée M, Laquerrière A, Duyckaerts C, Delisle MB, Streichenberger N, Lannes B, Frebourg T, Hannequin D, Campion D. 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Lott IT, Head E. Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat Rev Neurol. 2019 Mar;15(3):135-147. PubMed.
- 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.
- 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
Protein Diagram
Primary Papers
- Wallon D, Rousseau S, Rovelet-Lecrux A, Quillard-Muraine M, Guyant-Maréchal L, Martinaud O, Pariente J, Puel M, Rollin-Sillaire A, Pasquier F, Le Ber I, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Thomas-Antérion C, Paquet C, Moreaud O, Gabelle A, Sellal F, Sauvée M, Laquerrière A, Duyckaerts C, Delisle MB, Streichenberger N, Lannes B, Frebourg T, Hannequin D, Campion D. 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.
Other mutations at this position
- APP Duplication 1104 [APP-APP]
- APP Duplication ALZ-254 [POTED-ADAMTS5]
- APP Duplication ALZ-478 [LINC00158-EIF4A1P]
- APP Duplication EXT 1853 [MRPL39-CYYR1]
- APP Duplication EXT 2066 [MRPL39-APP]
- APP Duplication EXT-006 [HSPA13-GRIK1]
- APP Duplication EXT-019 [LINC00158-USP16]
- APP Duplication EXT-054 [USP25-ADAMTS1]
- APP Duplication EXT-1093 [AK124194-CYYR1]
- APP Duplication EXT-1230 [BTG3- ADAMTS5]
- APP Duplication EXT-1252 [LINC00158-ADAMTS1]
- APP Duplication EXT-145 [NCAM2-EIF4A1P]
- APP Duplication EXT-1516 [APP-ADAMTS1]
- APP Duplication EXT-1864 [TUBAP-ADAMTS1]
- APP Duplication EXT-187 [POTED-ADAMTS5]
- APP Duplication EXT-262 [JAM2-APP]
- APP Duplication EXT-279 [GABPA-ADAMTS1]
- APP Duplication EXT-298 [GABPA-CYYR1]
- APP Duplication EXT-773 [LINC00158-CYYR1]
- APP Duplication EXT-814 [NCAM2-ADAMTS5]
- APP Duplication EXT-857 [MRPL39-ADAMTS5]
- APP Duplication F009 [LINC00158-EIF4A1P]
- APP Duplication F019 [LINC00158-BACH1]
- APP Duplication F028 [MRPL39-APP]
- APP Duplication F037 [LINC00158-APP]
- APP Duplication F229 [NCAM2-EIF4A1P]
- APP Duplication PED 2945 [APP-CYYR1]
- APP Duplication PED 3281 [LINC00158-ADAMTS5]
- APP Duplication [APP-CYYR1]
- APP Duplication [JAM2-APP]
- APP Triplication [APP-APP]
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