Genetic Basis of Inherited Thrombophilia in Korea: A Single-Institution Experience.

Background: Inherited thrombophilia (HT) is a condition that genetically imposes a risk to develop thrombosis. It has been known that the genetic basis of IT is different between Caucasians and Asians; factor V Leiden mutation (R506Q) and the prothrombin gene mutation G20210A are major causes of HT among Caucasians, while they are extremely rare among Asians. Thus the deficiency of anticoagulant factors such as protein C (PC), protein S (PS), and antithrombin (AT) are believed to play a major role in Asians. Genetic study is important to confirm the diagnosis, since there are many acquired conditions including anticoagulant therapy that may mimic inherited form of deficiency. In this study, consecutive patients with a clinical and laboratory suspicion of IT were recruited for genetic diagnosis at a single institution, Samsung Medical Center, Seoul, Korea.

Materials and Methods: From December 2004 to July 2005, a total of 15 patients had presumptive diagnosis of IT; seven were suspected to have PC deficiency (activity, 43~ 51%), four PS deficiency (free Ag; 12~38%), and four AT deficiency (activity, 63~67%). All exons and their flanking sequences of the PROC gene, PROS1, or SERPINC1 were directly sequenced and analyzed.

Results: All seven patients with PC deficiency were shown to have a mutation in PROC. Of note, four of them had a common missense mutation, and the haplotype analysis using polymorphic markers showed that it is a mutation hot focus rather than a founder effect. Two other mutations were novel. Two of four patients with PS deficiency had a mutation in PROS1, each of which was novel. Three of four AT deficiency had a mutation in SERPINC1; one with a novel splice mutation and two shared a common splice mutation, which has not been reported, either. Overall, nine mutation carriers were detected through family study.

Conclusion: This study revealed the genetic basis, mutation spectrum, and the mutation detection rate of IT in consecutive Korean patients. Since diverse (known or novel) mutations underlie genetic deficiency of anticoagulants in Koreans, genetic studies employing direct sequencing for the whole gene are necessary to confirm the diagnosis, and for further family studies.