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Congenital factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder characterized by prolonged prothrombin time (PT) and reduced FVII coagulant activity (FVII: C). Here, we present the case of a middle-aged male patient with gastrointestinal bleeding, who exhibited prolonged PT and decreased FVII: C levels. Gene sequencing analysis revealed compound heterozygous mutations in the F7 gene: c.64G > A (p.V22I) and c.506-1G > A. Based on the laboratory results and gene sequencing, the patient was diagnosed as FVII deficiency. After adding recombinant activated FVII (rFVIIa) for several days, the laboratory indicators returned to normal and the bleeding symptoms were relieved. In subsequent validation studies, we also identified the c.506-1G > A mutation in his older sister and daughter. Importantly, this represents the first documented case where both mutations coexist concurrently. Additionally, our literature review reveals that approximately 50% of mutation types associated with congenital FVII deficiency are located on exon 9; however, there is no significant correlation between the reduction in FVII: C levels and severity of clinical symptoms based on EAHAD database analysis.

Congenital factor (F) VII deficiency is caused by mutations in the F7 gene. The p.Q160R variant manifests with bleeding episodes due to reduced FVII activity and antigen in patient plasma, most likely caused by protein misfolding and intracellular retention. As current replacement therapy is expensive and requires frequent intravenous injections, there is an unmet need for new and less invasive therapeutic strategies. Drug repurposing allows for rapid, more cost-effective discovery and implementation of new treatments, and identification of pharmacological enhancers of FVII variant activity would be of clinical importance. High-throughput screening of > 1800 FDA-approved drugs identified the orally available histone deacetylase inhibitor abexinostat and the inhaled surfactant tyloxapol as enhancers of FVII p.Q160R variant activity. The positive hits were verified in an in vitro cell model transiently expressing wild type or variant FVII and ex vivo in patients’ plasma. Both drugs showed a dose-response effect on FVII antigen and activity levels in conditioned cell medium and on FVII activity in patients’ plasma. In conclusion, the efficacy of the FDA-approved drugs abexinostat and tyloxapol in enhancing FVII variant activity constitute a proof of principle for high-throughput identification of drugs that may be feasible for novel treatment of FVII deficiency.

Congenital factor VII (FVII) deficiency is a rare genetic bleeding disorder characterized by deficient or reduced activity of coagulation FVII. It is caused by genetic variants in the F7 gene. We aimed to evaluate the rate of detection of pathogenic variants in the F7 gene in a large group of patients with FVII deficiency and investigate the correlations between the F7 genotype and FVII activity (FVII:C). Moreover, the influence of the common genetic variant rs6046: c.1238G>A; p.(Arg413Gln), designated as the M2 allele, on FVII:C was investigated. Genetic analysis of the F7 gene was performed on 704 index patients (IPs) using either direct Sanger- or next-generation sequencing. Genetic variants were detected in 390 IPs, yielding a variant detection rate (VDR) of 55%. Notably, the VDR exhibited a linear decline with increasing FVII:C levels. We identified 124 genetic variants, of which 48 were not previously reported. Overall, the frequency of the M2 allele was considerably higher in patients with mild deficiency (FVII:C > 20 IU/dl). Furthermore, IPs lacking an identified pathogenic variant exhibited a significantly higher prevalence of the M2 allele (69%) compared to IPs with a disease-causing variant (47%). These results strongly support the association of the M2 allele with decreased FVII:C levels. This study shows the utility of FVII:C as a predictive marker for identifying pathogenic variants in patients with FVII deficiency. The M2 allele contributes to the reduction of FVII:C levels, particularly in cases of mild deficiency.

Abstract Hereditary factor VII (FVII) deficiency is an uncommon autosomal recessive disorder associated with mutations in the F7 gene, and laboratory investigations usually reveal isolated prolongation in prothrombin time (PT)/international normalized ratio (INR). Venom-induced consumptive coagulopathy (VICC) is distinguished by the activation of the coagulation pathway, which is triggered by procoagulant toxins in snake venom. Diagnosing snakebites in patients with hereditary FVII deficiency presents a challenge because prolonged time PT/INR is considered the most valuable diagnostic method for VICC. Therefore, it is possible that certain patients may not promptly receive an accurate diagnosis of hereditary FVII deficiency. We present a pedigree featuring hereditary FVII deficiency, which was diagnosed through Sanger sequencing, following a bamboo leaf green snake bite.

Background Congenital coagulation factor VII (FVII) deficiency is a rare, autosomal‐recessive haemorrhagic disorder with an estimated incidence of 1:500,000. This disorder is caused by mutations in the F7 gene. Case description Here, we report a pedigree of congenital FVII deficiency. The proband was a 30‐year‐old female with severely low FVII activity and a history of menorrhagia and epistaxis since her childhood who was subsequently diagnosed with congenital compound heterozygous FVII deficiency. A genetic study revealed a novel combination of compound heterozygous mutations (c.64G 〉 A, p.Gly22Ser and c.1027G 〉 A, p.Gly343Ser). Her father and older son had the c.64G 〉 A, p.Gly22Ser (heterozygous) mutation. Her mother and younger son had the c.1027G 〉 A, p.Gly343Ser (heterozygous) mutation. The predicted results of PolyPhen‐2 and MutationTaster indicated that these mutations were probably damaging and disease‐causing, respectively. Conclusion In this study, we identified a novel combination of genetic mutations that could expand the mutant library and help in elucidating the pathogenesis of hereditary human coagulation FVII deficiency. A novel combination of compound heterozygous mutations was reported for the first time in Chinese individuals. We report a pedigree of congenital FVII deficiency. A genetic study revealed a novel combination of compound heterozygous mutations (c.64G 〉 A, p.Gly22Ser and c.1027G 〉 A, p.Gly343Ser). Predicted structure of FVII protein shows it could enhance the polarity. The steric collision and the new hydrogen bonds would lead to a reduction in the stability of the protease domain.

Introduction Hereditary human coagulation factor VII (FVII) deficiency is an inherited autosomal recessive hemorrhagic disease involving mutations in the F7 gene. The sites and types of F7 mutations may influence the coagulation activities of plasma FVII (FVII: C) and severity of hemorrhage symptoms. However, the specific mutations that impact FVII activity are not completely known. Methods We tested the coagulation functions and plasma activities of FVII in seven patients recruited from six families with hereditary FVII deficiency and sequenced the F7 gene of the patients and their families. Then, we analyzed the genetic information from the six families and predicted the structures of the mutated proteins. Results In this study, we detected 11 F7 mutations, including four novel mutations, in which the mutations p.Phe84Ser and p.Gly156Cys encoded the Gla and EGF domains of FVII, respectively, while the mutation p.Ser339Leu encoded the recognition site of the enzymatic protein and maintained the conformation of the catalytic domain structure. Meanwhile, the mutation in the 5′ untranslated region (UTR) was closely associated with the mRNA regulatory sequence. Conclusion We have identified novel genetic mutations and performed pedigree analysis that shed light on the pathogenesis of hereditary human coagulation FVII deficiency and may contribute to the development of treatments for this disease. In this study, we performed coagulation index tests and gene sequencing on 7 hereditary FVII deficiency patients and their family members to explain the pathogenesis of the disease based on the analysis of their genetic information. Also, we compared the structures of newly discovered mutant proteins with the wild type and predicted their pathogenicity. To sum up, this study expands our insight on the pathogenesis of hereditary human coagulation FVII deficiency.

Tailored approaches to restore defective transcription responsible for severe diseases have been poorly explored. We tested transcription activator-like effectors fused to an activation domain (TALE-TFs) in a coagulation factor VII (FVII) deficiency model. In this model, the deficiency is caused by the −94C > G or −61T > G mutation, which abrogate the binding of Sp1 or HNF-4 transcription factors. Reporter assays in hepatoma HepG2 cells naturally expressing FVII identified a single TALE-TF (TF4) that, by targeting the region between mutations, specifically trans-activated both the variant (>100-fold) and wild-type (20–40-fold) F7 promoters. Importantly, in the genomic context of transfected HepG2 and transduced primary hepatocytes, TF4 increased F7 mRNA and protein levels (2- to 3-fold) without detectable off-target effects, even for the homologous F10 gene. The ectopic F7 expression in renal HEK293 cells was modestly affected by TF4 or by TALE-TF combinations. These results provide experimental evidence for TALE-TFs as gene-specific tools useful to counteract disease-causing promoter mutations.

Background Factor VII deficiency is a rare inherited bleeding disorder that has similar clinical presentation to hemophilia. Case report A 7-year-old male child of African origin experienced recurrent nasal bleeding since 3 years of age and recurrent swelling of the joints that was remarkable at the age of 5–6 years. He received multiple blood transfusions and has been managed as a patient with hemophilia until he presented to our facility. Reviewed evaluation of the patient revealed abnormal prothrombin and normal activated partial thromboplastin time, FVII analysis showed activity level of less than 1%, and the diagnosis of FVII deficiency was made. The patient was treated with fresh frozen plasma, vitamin K injection, and tranexamic tablets. Conclusion Even though factor VII deficiency is an extremely rare bleeding disorder, it does occur in our setting. This case highlights the need for clinicians to consider this condition when faced with challenging patients presenting with bleeding disorders.

Background Preimplantation genetic diagnosis (PGD) is a powerful tool for preventing the transmission of Mendelian disorders from generation to generation. However, PGD only can identify monogenically inherited diseases, but not other potential monogenic pathologies. We aimed to use PGD to deliver a healthy baby without congenital FVII deficiency or other common Mendelian diseases in a couple in which both individuals carried a deleterious mutation in the F7 gene. Methods After both members of the couple were confirmed to be carriers of the F7 gene mutation by Sanger sequencing, expanded carrier screening (ECS) for 623 recessive inheritance diseases was performed to detect pathological mutations in other genes. PGD and preimplantational genetic screening (PGS) were employed to exclude monogenic disorders and aneuploidy for their embryos. Results ECS using targeted capture sequencing technology revealed that the couple carried the heterozygous disease-causative mutations c.3659C > T (p.Thr1220Ile) and c.3209G > A (p.Arg1070Gln) in the CFTR gene. After PGD and PGS, one of their embryos that was free of congenital FVII deficiency, cystic fibrosis (CF) and aneuploidy was transferred, resulting in the birth of a healthy 3200 g male infant. Conclusion We successfully implemented PGD for congenital FVII deficiency and PGD after ECS to exclude CF for the first time to the best of our knowledge. Our work significantly improved the reproductive outcome for the couple and provides a clear example of the use of ECS combined with PGD to avoid the delivery of offspring affected not only by identified monogenically inherited diseases but also by other potential monogenic pathologies and aneuploidy.

Acquired isolated factor VII deficiency is a rare bleeding disorder and has been reported in 31 cases. This is in contrast to congenital factor VII deficiency, which while also infrequent is the most common rare congenital bleeding disorder. Acquired isolated factor VII deficiency has been described primarily in patients with solid malignancies, sepsis, and in the presence of anti-factor VII autoantibodies. We report a case of acute myelogenous leukemia with an associated trisomy 8 cytogenetic abnormality presenting with factor VII deficiency. The factor VII deficiency cleared after induction chemotherapy and with the disappearance of the cytogenetic and molecular abnormalities. We discuss a possible link between trisomy 8 and vitamin K metabolism, which might result in acquired factor VII deficiency in acute myelogenous leukemia.