Abstract
The strategies of classifying APP, PSEN1, and PSEN2 variants varied substantially in the previous studies. We aimed to re-evaluate these variants systematically according to the American college of medical genetics and genomics and the association for molecular pathology (ACMG-AMP) guidelines. In our study, APP, PSEN1, and PSEN2 variants were collected by searching Alzforum and PubMed database with keywords “PSEN1,” “PSEN2,” and “APP.” These variants were re-evaluated based on the ACMG-AMP guidelines. We compared the number of pathogenic/likely pathogenic variants of APP, PSEN1, and PSEN2. In total, 66 APP variants, 323 PSEN1 variants, and 63 PSEN2 variants were re-evaluated in our study. 94.91% of previously reported pathogenic variants were re-classified as pathogenic/likely pathogenic variants, while 5.09% of them were variants of uncertain significance (VUS). PSEN1 carried the most prevalent pathogenic/likely pathogenic variants, followed by APP and PSEN2. Significant statistically difference was identified among these three genes when comparing the number of pathogenic/likely pathogenic variants (P < 2.2 × 10–16). Most of the previously reported pathogenic variants were re-classified as pathogenic/likely pathogenic variants while the others were re-evaluated as VUS, highlighting the importance of interpreting APP, PSEN1, and PSEN2 variants with caution according to ACMG-AMP guidelines.
Highlights
Being the most common neurodegenerative disease, Alzheimer’s disease (AD) is hallmarked by insidious cognitive impairment
We found that 94.91% of previously reported pathogenic variants were re-evaluated as pathogenic/likely pathogenic variants, and the others were VUS variants
The most prevalent pathogenic/likely pathogenic variants were located in the PSEN1 gene, followed by the amyloid precursor protein (APP) gene and the PSEN2 gene
Summary
Being the most common neurodegenerative disease, Alzheimer’s disease (AD) is hallmarked by insidious cognitive impairment. With the coming of an aging society, the number of AD is increasing rapidly (Saez-Atienzar and Masliah, 2020). Only three causative genes have been identified in the pathogenesis of AD, including amyloid precursor protein (APP), presenilin (PSEN1), and presenilin (PSEN2). Re-evaluation AD Causative Genes’ Variants protein precursor, whose proteolysis generates amyloid-β(Aβ), a key component of amyloid plaque. Presenilin-1 and presenilin-2 are encoded by PSEN1 and PSEN2, respectively. Both of them are subunits of γ-secretase and associated with either the increase of Aβ or the raised ratio of Aβ42 over Aβ40 (Loy et al, 2014), causing the formation of amyloid plaques and leading to the development of AD (Sun et al, 2017)
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