Bioinformatic analysis of human ZPR1 gene pathogenic exome mutations

Area of Science:

• Genomics and Bioinformatics
• Human Genetics
• Molecular Biology

Background:

• Advanced sequencing technologies accelerate the identification of genetic variants linked to human disorders.
• Interpreting the functional impact of novel exome variants on diverse phenotypes remains a significant challenge.
• Understanding gene-specific variant impact, such as in the zinc finger protein 1 (ZPR1) gene, is crucial for genetic diagnostics.

Approach:

• Developed a multi-tiered computational method combining variant effect prediction, protein stability analysis, and ACMG/AMP guidelines.
• Utilized in silico tools for structural analysis to identify critical amino acid residues in ZPR1 zinc finger domains.
• Examined 223 germline ZPR1 exome variants to assess their pathogenicity and population frequencies.

Key Points:

• Identified specific amino acid residues in ZPR1's zinc finger domains sensitive to pathogenic substitutions.
• Uncovered significant ethnic variations in the frequency of heterozygous harmful ZPR1 variants, with higher prevalence in African/African Americans (0.34%) compared to Ashkenazi Jewish (0.04%).
• Discovered three homozygous ZPR1 variant carriers in European and South Asian populations, indicating a potentially higher occurrence in these groups.

Conclusions:

• The study provides a robust framework for evaluating the pathogenicity of novel exome variants, exemplified by ZPR1.
• Revealed substantial ethnic disparities in the frequency of harmful ZPR1 variants, highlighting the need for diverse population data in genetic studies.
• The findings underscore the importance of investigating ZPR1 variants further due to their potential association with genetic disorders and observed population-specific frequencies.