4.6 Article

APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines

期刊

FRONTIERS IN AGING NEUROSCIENCE
卷 13, 期 -, 页码 -

出版社

FRONTIERS MEDIA SA
DOI: 10.3389/fnagi.2021.695808

关键词

Alzheimer's disease; ACMG-AMP guidelines; APP; PSEN1; PSEN2; re-evaluation

资金

  1. National Key R&D Program of China [2020YFC2008500]
  2. National Natural Science Foundation of China [82071216]

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The study systematically re-evaluated APP, PSEN1, and PSEN2 variants, showing that PSEN1 carried the most prevalent pathogenic/likely pathogenic variants, emphasizing the importance of interpreting these variants with caution according to ACMG-AMP guidelines.
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 x 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.

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