Genetic Variants in the Protein S ( ) Gene and Protein S Deficiency in a Danish Population.

Protein S (PS) deficiency is a risk factor for venous thromboembolism (VTE) and can be caused by variants of the gene encoding PS ( ). This study aimed to evaluate the clinical value of molecular analysis of the gene in PS-deficient participants. We performed Sanger sequencing of the coding region of the gene and multiplex ligation-dependent probe amplification to exclude large structural rearrangements. Free PS was measured by a particle-enhanced immunoassay, while PS activity was assessed by a clotting method. A total of 87 PS-deficient participants and family members were included. In 22 index participants, we identified 13 coding variants. Five variants were novel. In 21 index participants, no coding sequence variants or structural rearrangements were identified. The free PS level was lower in index participants carrying a variant compared with index participants with no variant (0.51 [0.32-0.61] vs. 0.62 [0.57-0.73] × 10 IU/L;  < 0.05). The p.(Thr78Met) variant was associated with only slightly decreased free PS levels (0.59 [0.53-0.66] × 10 IU/L) compared with the p.(Glu390Lys) variant (0.27 [0.24-0.37] × 10 IU/L,  < 0.01). The frequency of VTE in participants with a coding variant was 43 and 17% in the group with normal gene (  = 0.05). In conclusion, we report 13 coding variants including five novel variants. PS levels differ by variant and the frequency of VTE was higher when a coding variant was present. Hence, molecular analysis of the gene may add clinical value in the diagnostic work-up of PS deficiency.