Exploring genetic drivers of unexplained venous thromboembolism through whole-exome sequencing

Abstract

Venous thromboembolism (VTE) is a complex multifactorial disorder in which the contribution of genetic and non-genetic risk factors is well recognized, yet standard thrombophilia testing is unable to explain a substantial proportion of cases. To explore additional genetic contributors, we performed whole-exome sequencing (WES) in 35 patients with recurrent and/or severe VTE in whom routine diagnostic evaluation failed to identify risk factors. Variants were first screened against established thrombophilia-associated loci using clinical classification tools, while the remaining variants were prioritized through machine learning-based algorithms and Bayesian statistical methods combined with pathway enrichment and network analysis. Pathogenic or likely pathogenic variants were identified in PROC (c.70 + 1G > A, p.Ala43Thr, p.Pro321Leu), PROS1 (p.Tyr234Cys), and ADAMTS13 (p.Val832AlafsTer12). Additional candidate variants were detected in F5 (p.Arg376Ser, two patients) and F7 (p.Arg88Trp, p.Ala354Val), the latter previously associated with bleeding disorders. In the remaining patients, prioritized variants were predominantly enriched in pathways related to blood coagulation, including processes involving FVIII/von Willebrand factor (vWF) interactions and platelet biology. These included variants in STAB2, LRP1, ARSA, THBS1, SVEP1, LRP5, TLN1, MYH9, FERMT3, and PLCG1. Our findings indicate that, in addition to established thrombophilia genes, variants affecting auxiliary pathways, particularly those involving vWF and platelet biology, may contribute to unexplained VTE.

Keywords: Bioinformatics; Platelets; Venous thromboembolism (VTE); Whole-exome sequencing (WES); von Willebrand factor (vWF).