Martina Mia Mitić1, Dušan Ušjak1, Mirjana Kovač2, Marija Cumbo1, Sofija Dunjić Manevski1, Branko Tomić1and Valentina Đorđević1*
1 Institute of Molecular Genetics and Genetic Engineering, Belgrade, Serbia
2 Blood Transfusion Institute of Serbia, Belgrade Serbia
martinamiamitic [at] imgge.bg.ac.rs
Abstract
The etiology of substantial number of thrombosis cases remains undetermined. Sequencing and comprehensive analysis of the entire exome in patients with idiopathic thrombosis enable the identification of novel gene variants potentially significant for disease onset and the discovery of previously unknown molecular mechanisms underlying this multifactorial condition. This study aimed to investigate synonymous genetic variants potentially linked to thrombosis. While previous studies predominantly focused on missense and stop gain variants, the role of synonymous variants in thrombosis susceptibility remains relatively overlooked.
The study included 50 subjects: 17 patients with recurrent idiopathic thrombosis and 33 controls from the general population. Whole exome sequencing (WES) was performed according to protocol of the Beijing Genomics Institute and subsequent FASTQ files were processed to obtain Variant Call Format (VCF) files with annotations. While the entire exome was examined, a panel of 55 genes was selected for more focused analysis. The data were filtered to extract only synonymous variants within the genes in this panel.
Statistical analyses were performed by creating contingency table counts in R and by applying weights and utilizing chi-square or Fisher’s exact tests in Python. A p value of p < 0.05 was defined as statistically significant. A total of 15 synonymous variants exhibiting statistical significance in the idiopathic thrombosis group were identified. Variants were detected in PLG, PROC, ABO, KNG1, ADAMTS13, ACE, HIVEP1 and F2 genes.
In conclusion, although the study exhibits considerable limitations due to the small sample size, the identification of significant synonymous variants underscored a potential association between thrombosis and these genetic determinants. Further studies with larger cohorts are imperative to validate and expand upon these initial findings.
Keywords: Thrombosis, Synonymous variants, Whole exome sequencing, Idiopathic thrombosis