Mutations

APP Duplication EXT-1252 [LINC00158-ADAMTS1]

Overview

Pathogenicity: Alzheimer's Disease : Not Classified, 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 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 1252), including three affected members spanning two generations, ranged from 54 to 58 years, and disease duration from two to eight years. The proband and a half-sister had dementia. In addition, the proband had probable cerebral amyloid angiopathy and a sister had stroke.

A ~1.4Mb duplication spanning eight genes from LINC00158 to ADAMTS1, including APP, was identified in a single family member 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/E3 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). Moreover, brain MRI of the proband revealed probable cerebral amyloid angiopathy with one intracerebral hemorrhage and 25 microbleeds (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 : 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.

PS1-M

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Duplication EXT-1252 [LINC00158-ADAMTS1]: 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-1252 [LINC00158-ADAMTS1]: 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-1252 [LINC00158-ADAMTS1]: 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: 14 Jul 2023

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

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

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. 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. 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.
  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. 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.
  8. 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.

External Citations

  1. Lott and Head, 2019

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  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.

Other mutations at this position

View Table

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.