Overview

Pathogenicity: Cerebral Amyloid Angiopathy : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PP1, PP4
Clinical Phenotype: Cerebral Amyloid Angiopathy
Position: (GRCh38/hg38):Chr21:25881339_25881338 TA>--
Position: (GRCh37/hg19):Chr21:27253650_27253649 TA>--
dbSNP ID: NA
Coding/Non-Coding: Non-Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Genomic Region: Exon 18, 3' UTR

Findings

This deletion variant in the 3' untranslated region of APP was found in one out of 90 cases with cerebral amyloid angiopathy (CAA) (Nicolas et al., 2015). The patient was diagnosed with probable CAA on the basis of clinical findings and imaging. In brief, at the age of 39 he developed multiple spontaneous cortical hemorrhages. These were bilateral subarachnoid hemorrhages resulting in delirium. Several lobar hematomas followed in subsequent months, along with cortical microbleeds, diffuse superficial siderosis, and white-matter hyperintensities. No other sequence abnormalities were detected at the APP locus. The patient's APOE genotype was ε3/ε4. He had no family history of CAA. His unaffected mother did not carry the variant, suggesting possible segregation with disease. DNA from the patient’s father was unavailable, as he had died suddenly at the age of 70. The mutation carrier was of sub-Saharan African origin and the variant was absent in 175 controls originating from this region, as well as from the gnomAD variant database (v2.1.1, Oct 2021).

Note, this variant is named according to its position in the 3' UTR of APP. Nucleotides 331 and 332 in the UTR are deleted.

Neuropathology

Unknown. Imaging revealed multiple hemorrhages and hematomas in the temporal, frontal, and parietal regions of the cortex. These were lobar and subarachnoid hemorrhages. Diffuse superficial siderosis was observed, along with cortical microbleeds and white-matter hyperintensities.

Biological Effect

This variant in the 3' UTR of APP is a two base pair (TA) deletion. This deletion occurs in a highly conserved region of the UTR. When cloned into a luciferase reporter, the variant increased APP expression approximately 1.5-fold over wild-type levels. APP mRNA was similarly elevated in patient's blood. Follow-up experiments indicated that this upregulation was at least partially attributable to changes in miRNA binding.

Pathogenicity

Cerebral Amyloid Angiopathy : Likely Pathogenic*

*Although not AD, the condition associated with this variant is inherited in an autosomal dominant manner, so its pathogenicity was classified using the ACMG guidelines.

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. Nicolas G, Wallon D, Goupil C, Richard AC, Pottier C, Dorval V, Sarov-Rivière M, Riant F, Hervé D, Amouyel P, Guerchet M, Ndamba-Bandzouzi B, Mbelesso P, Dartigues JF, Lambert JC, Preux PM, Frebourg T, Campion D, Hannequin D, Tournier-Lasserve E, Hébert SS, Rovelet-Lecrux A. Mutation in the 3'untranslated region of APP as a genetic determinant of cerebral amyloid angiopathy. Eur J Hum Genet. 2015 Apr 1; PubMed.

Further Reading

No Available Further Reading