PB0958 - Detection of new genetic variants in patients with idiopathic recurrent venous thrombosis

Monday, June 24, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

Martina Mia Mitic, MA

Junior researcher
Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade (UB)
Belgrade, Vojvodina, Serbia

Co-Author(s)

DU

Dusan Usjak

Research associate
Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade (UB)
Belgrade, Vojvodina, Serbia
MC

Marija Cumbo

Research assistant
Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade (UB)
Belgrade, Vojvodina, Serbia
SD

Sofija Dunjic Manevski

Research assistant
Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade (UB)
Belgrade, Vojvodina, Serbia
BT

Branko Tomic

Associate research professor
Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade (UB)
Belgrade, Vojvodina, Serbia
MK

Mirjana Kovac

Full research professor
Blood Transfusion Institute of Serbia
Belgrade, Vojvodina, Serbia
VD

Valentina Djordjevic

Full research professor
Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade (UB)
Belgrade, Vojvodina, Serbia

Background: Despite significant advancements in molecular genetics knowledge, identification of genetic risk factors of familial thrombophilia remains a major challenge.

Aims: The current study aimed to identify new putative genetic biomarkers that would contribute to elucidating the causes of idiopathic venous thrombosis.

Methods: The study included 16 patients diagnosed with recurrent idiopathic thrombotic events, patiently selected from the repository of the Laboratory for Molecular Biology, IMGGE, which includes about 5000 patients with thrombotic events. All patients had a positive family history of thrombophilia, and repeated thrombotic events, with the first occurring at an early age. The patients were screened for hemostatic parameters and subjected to whole exome sequencing (WES) analysis. Generated variant calling files (VCFs) were searched for thrombophilia risk factors using clinical interpretation tools (ClinVar and ACMG), gene ontology and interaction databases (OMIM and STRING), and in silico prediction tools (CADD Phred, PolyPhen-2 and SIFT). Damaging potential of selected missense variants was further analyzed based on predicted modulation of protein intramolecular and intermolecular, as well as protein-metal interactions by using VarMap web tool.

Results: Notably, increased factor VIII concentrations were detected in 12 patients, whereas 1 patient had elevated tissue factor. Putative thrombophilia risk factors were detected in 8 patients. These included rare heterozygous missense or stop-gain variants in F5, SERPINC1, KNG1 and HABP2 genes. Association between these variants and venous thrombosis has not yet been documented and requires further studies. Besides, potentially significant missense variants were also found in ADAMTS13, PLAT, APOH, F13B and SRRM2 genes.

Conclusion(s): Use of WES analysis has led to identification of new putative thrombophilia risk factors in investigated patients with recurrent idiopathic thrombotic events. Functional analysis will be performed to further estimate significance of the selected genetic variants.