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

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 assays, consistent with a potential protective effect. Together, this study highlights the complexities associated with classification of rare variants in ADAD genes.

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Publication Details

Journal
Neurotherapeutics
Published
2025-01-27
DOI
https://doi.org/10.1016/j.neurot.2025.e00527
Citations
5
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
9.09

Funders

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article

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

Alan E. Renton, Celeste M M. Karch, Cyril P. Pottier, Randall John Bateman et al.
5 citations
Neurotherapeutics
Genomics and Rare Diseases
9.09
article

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

Alan E. Renton, Celeste M M. Karch, Cyril P. Pottier, Randall John Bateman, Jacob Marsh, Carlos C Cruchaga, Kevin M. Bowling, Guangming Huang, Ellen Ziegemeier, Gregory Scott Day, Eric McDade, Jorge J. Llibre‐Guerra, T. Blake Ball
article en
5 citations

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 assays, consistent with a potential protective effect. Together, this study highlights the complexities associated with classification of rare variants in ADAD genes.

NeurotherapeuticsVol. 22(3)
Washington University in St. Louis (US), Mayo Clinic in Florida (US)
Alzheimer's Association, Fondation Brain Canada, Japan Agency for Medical Research and Development, Korea Health Industry Development Institute, Deutsches Zentrum für Neurodegenerative Erkrankungen, Ministry of Science and ICT, South Korea, Fleni, Canadian Institutes of Health Research, Instituto de Salud Carlos III, National Institute on Aging
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Openalex Percentile: Top 3%
Genomics and Rare Diseases
9.09
DOIOpen Access PDFOpenAlex
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