Alternative titles; symbols
DO: 0080839;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq27.1 | {Warfarin sensitivity} | 301052 | X-linked | 3 | F9 | 300746 |
A number sign (#) is used with this entry because of evidence that warfarin sensitivity can be conferred by variation in the F9 gene (300746) on chromosome Xq27.
Warfarin is a widely prescribed anticoagulant for the prevention of thromboembolic diseases for subjects with deep vein thrombosis, atrial fibrillation, or mechanical heart valve replacement. The dose requirement is highly variable, both interindividually and interethnically (Yuan et al., 2005).
Chu et al. (1996) reported a 49-year-old Caucasian male patient who was referred for evaluation of bleeding complications that developed during anticoagulation with warfarin. The patient had a congenital bicuspid aortic valve with accompanying aortic stenosis and regurgitation. After insertion of an artificial valve, he developed bleeding complications when he was given warfarin for anticoagulation. The patient's family history was negative for bleeding diatheses. The patient had mild Charcot-Marie-Tooth disease and several members of his family in several generations were also affected. The proband had a factor IX activity level of more than 100% when not receiving warfarin and less than 1% when receiving warfarin, at a point where other vitamin K-dependent factors were at 30 to 40% activity levels.
Oldenburg et al. (1997) reported 3 patients in whom mutations in the factor IX propeptide were found to cause severe bleeding during coumarin therapy. Strikingly, the bleeding occurred within the therapeutic ranges of the prothrombin time (PT) and international normalized ratio (INR). In all 3 patients, coumarin therapy caused an unusually selective decrease of factor IX activity to levels below 1 to 3%. Upon withdrawal of coumarin, factor IX levels increased to subnormal or normal values of 55, 85 and 125%, respectively.
Pezeshkpoor et al. (2018) reported 18 patients, including 11 patients previously reported by Oldenburg et al. (2001), with mutations in the F9 propeptide and a bleeding phenotype during anticoagulation therapy with vitamin K antagonists. During the course of coumarin treatment, all 18 patients had an abnormally prolonged activated partial thromboplastin time (aPTT) and a disproportionate reduction of FIX:C. All 18 patients exhibited a new onset of bleeding symptoms of varying severity subsequent to initiating coumarin treatment.
In a 49-year-old patient who was found to have warfarin sensitivity, Chu et al. (1996) identified an A-10T mutation in the propeptide of the factor IX gene (A37T; 300746.0102). The mutation was found by direct sequence analysis of amplified genomic DNA from all 8 exons and exon-intron junctions of F9.
In 3 patients with warfarin sensitivity, Oldenburg et al. (1997) identified mutations in the F9 gene: the previously identified A37T mutation in 1 patient and an A-10V mutation (A37V; 300746.0103) in the others.
Pezeshkpoor et al. (2018) identified the A37T mutation in the F9 gene in 11 patients with X-linked warfarin sensitivity, including 6 patients previously reported by Oldenburg et al. (2001), and the A37V mutation in 7 patients, including 5 patients previously reported by Oldenburg et al. (2001). Expression of F9 containing the A37T mutation or the A37V mutation in HEK293T cells resulted in a reduction in the FIX:C ratio and a reduced half maximal inhibitory concentration (IC50) for warfarin compared to HEK293T cells transfected with wildtype F9. This indicated a sensitivity to warfarin conferred by both mutations, with A37V conferring less warfarin sensitivity than A37T.
Chu, K., Wu, S.-M., Stanley, T., Stafford, D. W., High, K. A. A mutation in the propeptide of factor IX leads to warfarin sensitivity by a novel mechanism. J. Clin. Invest. 98: 1619-1625, 1996. [PubMed: 8833911] [Full Text: https://doi.org/10.1172/JCI118956]
Oldenburg, J., Kriz, K., Wuillemin, W. A., Maly, F. E., von Felten, A., Siegemund, A., Keeling, D. M., Baker, P., Chu, K., Konkle, B. A., Lammle, B., Albert, T. Genetic predisposition to bleeding during oral anticoagulant therapy: evidence for common founder mutations (FIXVal-10 and FIXThr-10) and an independent CpG hotspot mutation (FIXThr-10). Thromb. Haemost. 85: 454-457, 2001. [PubMed: 11307814]
Oldenburg, J., Quenzel, E.-M., Harbrecht, U., Fregin, A., Kress, W., Muller, C. R., Hertefelder, H.-J., Schwaab, R., Brackmann, H.-H., Hanfland, P. Missense mutations at ala-10 in the factor IX propeptide: an insignificant variant in normal life but a decisive cause of bleeding during oral anticoagulant therapy. Brit. J. Haemat. 98: 240-244, 1997. [PubMed: 9233593] [Full Text: https://doi.org/10.1046/j.1365-2141.1997.2213036.x]
Pezeshkpoor, B., Czogalla, K. J., Caspers, M., Berkemeier, A.-C., Liphardt, K., Ghosh, S., Kellner, M., Ulrich, S., Pavlova, A., Oldenburg, J. Variants in FIX propeptide associated with vitamin K antagonism hypersensitivity: functional analysis and additional data confirming the common founder mutations. Ann. Hemat. 97: 1061-1069, 2018. [PubMed: 29450643] [Full Text: https://doi.org/10.1007/s00277-018-3264-2]
Yuan, H.-Y., Chen, J.-J., Lee, M. T. M., Wung, J.-C., Chen, Y.-F., Charng, M.-J., Lu, M.-J., Hung, C.-R., Wei, C.-Y., Chen, C.-H., Wu, J.-Y., Chen, Y.-T. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum. Molec. Genet. 14: 1745-1751, 2005. [PubMed: 15888487] [Full Text: https://doi.org/10.1093/hmg/ddi180]