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

• Published in: Frontiers in aging neuroscience Vol. 13; p. 695808
• Main Authors: Xiao, Xuewen, Liu, Hui, Liu, Xixi, Zhang, Weiwei, Zhang, Sizhe, Jiao, Bin
• Format: Journal Article
• Language: English
• Published: Lausanne Frontiers Research Foundation 18.06.2021; Frontiers Media S.A
• Subjects: ACMG-AMP guidelines; Aging; Alzheimer's disease; APP; Biomarkers; Classification; Mutation; Neurodegenerative diseases; Neuroscience; Older people; PSEN1; PSEN2; re-evaluation; Statistical analysis
• ISSN: 1663-4365; 1663-4365
• DOI: 10.3389/fnagi.2021.695808

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.