Evaluating pathogenicity of variants of unknown significance in APP, PSEN1, and PSEN2.

ABSTRACT: Autosomal dominant Alzheimer's disease (ADAD) is driven by rare variants in APP, PSEN1, and PSEN2. Although more than 200 pathogenic variants in these genes are known to cause ADAD, other variants are benign, may act as risk factors, or may even reduce Alzheimer's disease risk (e.g. protective). Classifying novel variants in APP, PSEN1, or PSEN2 as pathogenic, risk, benign, or protective is a critical step in evaluating disease risk profiles which further impacts eligibility for clinical trials focused on the ADAD population. Here, we classify 53 novel variants in APP, PSEN1, and PSEN2 based on bioinformatic data and cell-based assays. We identified 6 benign variants, 2 risk variants, and 32 likely pathogenic variants. Thirteen variants were associated with reduced Aβ levels in cell-based

SUBMITTER: Marsh JA 

PROVIDER: S-EPMC12047396 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature