| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq28 | Thrombophilia 13, X-linked, due to factor VIII defect | 301071 | 3 | F8 | 300841 |
A number sign (#) is used with this entry because of evidence that X-linked thrombophilia due to factor VIII defect (THPH13) is caused by mutation in the F8 gene (300841) on chromosome Xq28.
X-linked thrombophilia due to factor VIII defect (THPH13) is associated with markedly elevated F8 levels and severe thrombophilia (summary by Simioni et al., 2021).
Simioni et al. (2021) described 7 individuals from 2 Italian families with thrombophilia. The proband from family A (patient II:3) presented at 31 years of age with a deep vein thrombosis (DVT) in the leg and a pulmonary embolus (PE) following a cesarean section. She was treated with low molecular weight heparin (LMWH) and then with warfarin for 6 months. At age 44 years, she developed a DVT in the left leg, which was treated with warfarin for 1 year. Laboratory testing demonstrated elevated factor VIII levels and normal von Willebrand factor. She had another DVT in the left leg at age 46 years and had long-term warfarin treatment, but at age 52 years, she developed recurrent DVT in the leg and a PE. Her mother (patient I:3) died from a PE at age 48 years after a leg fracture and immobilization. A maternal aunt (patient I:4) had a DVT in her left leg and PE at age 49 years after immobilization for a left knee injury. She also developed saphenous vein thrombosis in the leg. A maternal cousin (patient II:6) developed a saphenous vein thrombosis and common femoral DVT in the right leg at age 43 years. Laboratory testing demonstrated elevated factor VIII levels in the maternal aunt and cousin. The proband from family B (patient II:1) experienced a DVT and PE at age 21 years. He was treated with LMWH and warfarin for 1 year. At age 31 years, he had another PE. After initial treatment with LMWH, lifelong warfarin therapy was recommended. His 66-year-old mother had a popliteal DVT after cesarean section at age 24 years. She also had a saphenous vein thrombosis in the right leg. Laboratory testing demonstrated elevated factor VIII and normal von Willebrand factor levels in the proband, his mother, and his asymptomatic daughter.
The transmission pattern of THPH13 in the family reported by Simioni et al. (2021) was consistent with X-linked dominant inheritance.
Shen et al. (2013) evaluated F8 activity and F8 gene copy number in 179 patients with venous thromboembolism and 176 healthy controls. Patients with venous thromboembolism had significantly higher F8 activity compared to controls and also had a significantly greater number of copies of the F8 gene. F8 activity was also correlated to F8 gene copy number in patients versus controls, although this was not true for every individual patient. The F8 copy number was significantly higher in males compared to females.
In 7 individuals from 2 Italian families with THPH13, Simioni et al. (2021) identified a tandem duplication in the factor VIII gene (300841.0272). The 2 families shared a 3-Mb haplotype, indicating a shared common ancestor. F8 mRNA was increased in patient lymphocytes. Increased transcriptional activity of fragments of the duplicated region was demonstrated by luciferase assay and was highest in a region (region C) that overlapped a major DNase I hypersensitivity cluster.
Shen, W., Gu, Y., Zhu, R., Zhang, L., Zhang, J., Ying, C. Copy number variations of the F8 gene are associated with venous thromboembolism. Blood Cells Molec. Dis. 50: 259-262, 2013. [PubMed: 23403259] [Full Text: https://doi.org/10.1016/j.bcmd.2013.01.004]
Simioni, P., Cagnin, S., Sartorello, F., Sales, G., Pagani, L., Bulato, C., Gavasso, S., Nuzzo, F., Chemello, F., Radu, C. M., Tormene, D., Spiezia, L., Hackeng, T. M., Campello, E., Castoldi, E. Partial F8 gene duplication (factor VIII Padua) associated with high factor VIII levels and familial thrombophilia. Blood 137: 2383-2393, 2021. [PubMed: 33275657] [Full Text: https://doi.org/10.1182/blood.2020008168]