Protein S Deficiency via the PROS1 Gene

Protein S deficiency is a disorder that increases the risk of developing abnormal clots, especially deep vein thrombosis (DVT) within the legs and arms. Symptoms can range greatly from asymptomatic to life-threatening with severe clotting called purpura fulminans appearing shortly after birth. The vast clinical spectrum of Protein S deficiency is due to the influence of environmental factors including increased age, surgery, inactivity, pregnancy, smoking, and oral contraceptives as well as other genetic risk factors such as Factor V Leiden and Prothrombin 20210G>A (Varga and Kujovich 2012). Mild Protein S deficiency is the most prevalent form, occurring in about 1 in 500 individuals. Protein S deficiency may also be acquired through chronic inflammation, liver disease, and vitamin K deficiency, making diagnosis of the hereditable form more difficult (Marlar and Gausman 2011). Anticoagulation therapies such as warfarin have been used to mitigate clotting in patients with Protein S deficiency. Genetic testing may aid in differential diagnosis between inherited and acquired forms of Protein S deficiency as well as from protein C deficiency, antithrombin deficiency, and other hypercoagulability disorders (Varga and Kujovich 2012).

Protein S deficiency is inherited in an autosomal dominant manner with variable penetrance due to mutations in the PROS1 gene. Rare compound heterozygous individuals typically have a severe form of the disease. Causative variants have been found throughout the PROS1 gene with missense, nonsense, insertions/deletions alterations, and splice site alterations representing 45%, 18%, 18%, and 14% of cases respectively (Gandrille et al. 2000; Biguzzi et al. 2005). Large deletions have been reported in a minority of cases (Pintao et al. 2009). Disease penetrance is incomplete, but linked to the degree of protein S activity loss. Thrombophilia risk is also increased through environmental factors and mutations in the F5 (Factor V Leiden), F2 (Prothrombin 20210), PROC, and SERPINC1 genes (Caspers M et al. 2012). Protein S functions as a cofactor for Protein C where together this complex functions to down regulate thrombin formation through degradation of pro-coagulation factors V and VIII (Marlar and Gausman 2011).

In a study of 53 patients with laboratory tests indicating Protein S deficiency (decreased Protein S activity or free antigen levels), mutation in the PROS1 gene was found in 38 (71%) (Biguzzi et al. 2005). Individuals with a familial history of thrombophilia identify a causative mutation in the F5, F2, SERPINC1, PROC, or PROS1 gene in about half of cases. Of those cases, PROS1 mutations represent between 1-3% of individuals with an identifiable hereditable cause for venous thromboembolism (Varga and Kujovich 2012).

This test provides full coverage of all coding exons of the PROS1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).