AUTHOR=Xiao Xuewen , Liu Hui , Liu Xixi , Zhang Weiwei , Zhang Sizhe , Jiao Bin 

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

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=13

YEAR=2021

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2021.695808

DOI=10.3389/fnagi.2021.695808

ISSN=1663-4365

ABSTRACT=<p>The strategies of classifying <italic>APP</italic>, <italic>PSEN1</italic>, and <italic>PSEN2</italic> 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, <italic>APP</italic>, <italic>PSEN1</italic>, and <italic>PSEN2</italic> 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 <italic>APP</italic>, <italic>PSEN1</italic>, and <italic>PSEN2</italic>. In total, 66 <italic>APP</italic> variants, 323 <italic>PSEN1</italic> variants, and 63 <italic>PSEN2</italic> 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). <italic>PSEN1</italic> carried the most prevalent pathogenic/likely pathogenic variants, followed by <italic>APP</italic> and <italic>PSEN2</italic>. Significant statistically difference was identified among these three genes when comparing the number of pathogenic/likely pathogenic variants (<italic>P</italic> &lt; 2.2 × 10<sup>–16</sup>). 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 <italic>APP</italic>, <italic>PSEN1</italic>, and <italic>PSEN2</italic> variants with caution according to ACMG-AMP guidelines.</p>