Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Cerebral Amyloid Angiopathy
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PP1
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy
Coding/Non-Coding: Both
DNA Change: Triplication
Expected RNA Consequence: Triplication
Expected Protein Consequence: Triplication
Genomic Region: Chromosome 21

Findings

This mutation, resulting in four copies of the APP gene due to a triplication of a segment of chromosome 21, was identified in a family with autosomal dominant, early onset cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD) (Grangeon et al., 2021). The proband had severe episodic memory loss, attention deficit, and executive dysfunction starting at age 39. His father had focal epilepsy seizures starting at age 37, followed by progressive behavioral problems and cognitive impairment including episodic memory loss. He died at 48 after a hemorrhagic event. Both affected individuals were diagnosed with probable AD.

The APP triplication was detected in the proband by quantitative multiplex PCR of short fluorescent fragments (QMPSF), fluorescence in situ hybridization, and array comparative genomic hybridization. It included the complete APP gene without additional genes. The proband’s APOE genotype was APOE3/E3 and he had no mutations in exons 16-17 of the APP gene. The proband’s unaffected mother had only two copies of APP indicating segregation of the triplication with disease. The father was not genotyped.

Neuropathology
A cerebral biopsy from the proband’s father showed abundant perivascular amyloid deposits, resulting in a diagnosis of CAA (Grangeon et al., 2021). Cerebral MRI in the early stages of disease showed hyperintensities in centrum semiovale, while subsequent imaging revealed acute bilateral temporal hematomas and posterior leukoencephalopathy.
In the proband, brain MRI showed multiple lobar microbleeds in the posterior fossa and occipital region and posterior periventricular leukoencephalopathy with hippocampal atrophy. Levels of AD biomarkers (Aβ42, Aβ40, tau, phospho-tau) in cerebrospinal fluid were consistent with AD.

Biological Effect
As expected, APP mRNA levels in blood were increased twofold in the proband compared with controls (Grangeon et al., 2021).

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

Paper Citations

1. Grangeon L, Cassinari K, Rousseau S, Croisile B, Formaglio M, Moreaud O, Boutonnat J, Le Meur N, Miné M, Coste T, Pipiras E, Tournier-Lasserve E, Rovelet-Lecrux A, Campion D, Wallon D, Nicolas G. Early-Onset Cerebral Amyloid Angiopathy and Alzheimer Disease Related to an APP Locus Triplication. Neurol Genet. 2021 Oct;7(5):e609. Epub 2021 Sep 8 PubMed.

Further Reading

No Available Further Reading