[Genetic diagnosis and bioinformatic analysis of a pedigree with inherited factor VII deficiency].
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ABSTRACT:
SUBMITTER: Guo Z
PROVIDER: S-EPMC7342163 | biostudies-literature | 2015 Feb
REPOSITORIES: biostudies-literature
Publications
[Genetic diagnosis and bioinformatic analysis of a pedigree with inherited factor VII deficiency].
Guo Zhiping Z Guo Jianli J Wu Ruihong R Zhang Yaofang Y Qin Xiuyu X Liu Xiue X Yang Linhua L
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 20150201 2
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Project description: Not available
| S-EPMC7449768 | biostudies-literature
Project description:Objective: To explore the molecular pathogenesis of a family with hereditary factor Ⅴ (FⅤ) deficiency. Methods: All the exons, flanking sequences, 5' and 3' untranslated regions of the F5 of the proband, and the corresponding mutation sites of the family members were analyzed via direct DNA sequencing. The CAT measurement was used to detect the amount of thrombin produced. The ClustalX software was used to analyze the conservation of mutation sites. The online bioinformatics software, Mutation Taster, PolyPhen-2, PROVEAN, LRT, and SIFT were applied to predict the effects of mutation sites on protein function. The Swiss-PdbViewer software was used to analyze the changes in the protein model and intermolecular force before and after amino acid variation. Results: The proband had a heterozygous missense mutation c.1258G>T (p.Gly392Cys) in exon 8 of the F5, and a heterozygous deletion mutation c.4797delG (p.Glu1572Lys fsX19) in exon 14, which results in a frameshift and produces a truncated protein. Her grandfather and father had p.Gly392Cys heterozygous variation, whereas her maternal grandmother, mother, little aunt, and cousin all had p.Glu1572LysfsX19 heterozygous variation. The ratio of proband's thrombin generation delay to peak time was significantly increased. Conservation analysis results showed that p.Gly392 was located in a conserved region among the 10 homologous species. Five online bioinformatics software predicted that p.Gly392Cys was pathogenic, and Mutation Taster also predicted p.Glu1572Lys fsX19 as a pathogenic variant. Protein model analysis showed that the replacement of Gly392 by Cys392 can lead to the extension of the original hydrogen bond and the formation of a new steric hindrance, which affected the stability of the protein structure. Conclusion: The c.1258G>T heterozygous missense mutation in exon 8 and the c.4797delG heterozygous deletion mutation in exon 14 of the F5 may be responsible for the decrease of FⅤ levels in this family.
| S-EPMC8071673 | biostudies-literature
Project description: Not available
| S-EPMC7342583 | biostudies-literature
Project description:BackgroundCongenital 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 descriptionHere, 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.ConclusionIn 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.
| S-EPMC9833959 | biostudies-literature
Project description:BackgroundCongenital factor VII deficiency (FVIID) is a rare autosomal recessive genetic disorder. The clinical manifestations of this deficiency vary greatly. Predicting the risk of bleeding during and after childbirth of pregnant women with congenital FVIID is difficult. Recombinant factor VIIa is the most common replacement therapy for FVIID. However, no unified diagnosis and treatment plan for pregnant women with congenital FVIID has been established.Case summaryWe report the clinical history of a pregnant woman who was considered to have congenital FVIID. Recombinant factor VIIa was prophylactically administered to the pregnant woman at the time of cervical fully opening. She successfully delivered a live infant without any complications, such as postpartum hemorrhage, neonatal abnormalities, and so on.ConclusionProphylaxis of recombinant factor VIIa during delivery can effectively reduce the incidence of postpartum hemorrhage among pregnant women with congenital FVIID associated with a high risk of bleeding.
| S-EPMC8316952 | biostudies-literature
Project description:Inherited bleeding disorders (IBDs) are the most frequent congenital diseases in the Colombian population; three of them are hemophilia A (HA), hemophilia B (HB), and von Willebrand Disease (VWD). Currently, diagnosis relies on multiple clinical laboratory assays to assign a phenotype. Due to the lack of accessibility to these tests, patients can receive an incomplete diagnosis. In these cases, genetic studies reinforce the clinical diagnosis. The present study characterized the molecular genetic basis of 11 HA, three HB, and five VWD patients by sequencing the F8, F9, or the VWF gene. Twelve variations were found in HA patients, four in HB patients, and 19 in WVD patients. From these variations a total of 25 novel variations were found. Disease-causing variations were used as positive controls for validation of the high-resolution melting (HRM) variant-scanning technique. This approach is a low-cost genetic diagnostic method proposed to be incorporated in developing countries. For the data analysis, we developed an accessible open-source code in Python that improves HRM data analysis with better sensitivity of 95% and without bias when using different HRM equipment and software. Analysis of amplicons with a length greater than 300 bp can be performed by implementing an analysis by denaturation domains.
| S-EPMC8625804 | biostudies-literature
Project description:IntroductionHereditary 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.MethodsWe 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.ResultsIn 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.ConclusionWe 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.
| S-EPMC8418470 | biostudies-literature
Project description:BackgroundCongenital factor VII (FVII) deficiency, a rare bleeding disorder resulting from mutations in the F7 gene with autosomal recessive inheritance, exhibits clinical heterogeneity that lacks a strong correlation with FVII:C levels. The objective of this study was to discern genetic defects and assess their associations with the clinical phenotype in a substantial cohort comprising 785 white women exhibiting FVII:C levels below the age-dependent cut-off percentage.Patients and methodsIndividuals with verified inherited factor VII deficiency underwent i) genotyping using the Sanger method and multiplex ligation-dependent probe amplification (MLPA) to identify F7 mutations, including common polymorphic variants. Additionally, they were ii) categorized based on clinical bleeding scores (BS). Thrombophilic variants and blood groups were also determined in the study participants.ResultsThe probands in this study encompassed both asymptomatic individuals (referred for a laboratory investigation due to recurrent prolonged prothrombin time; n = 221) and patients who manifested mild, moderate, or severe bleeding episodes (n = 564). The spectrum of bleeding symptoms included epistaxis, gum bleeding, gastrointestinal bleeding, hematuria, postoperative bleeding, and gynecologic hemorrhage. The median ISTH bleeding score (BS) recorded within a two-year period prior to the work-up was 2 (0-17). Notably, this score was significantly higher in symptomatic women compared to their asymptomatic counterparts (3 versus 0; p < 0.001). The corresponding PBAC score before hormonal treatment stood at 225 (5-1200), exhibiting a positive correlation with the ISTH BS (rho = 0.38; p = 0.001). Blood group O was more prevalent in symptomatic women compared to asymptomatic individuals (58 versus 42%; p = 0.01). Among the 329 women (42%), known and novel mutations in the F7 gene, encompassing coding regions, exon/intron boundaries, and the promoter region, were identified, while common polymorphisms were detected in 647 subjects (95%). Logistic regression analysis, adjusted for clinical and laboratory data (including blood group, FVII activity, the presence of F7 gene mutations and/or polymorphisms, thrombophilia status, and additional factor deficiencies) revealed that older age at referral (increase per year) (odds/95% CI: 1.02/1.007-1.03), the presence of blood group O (odds/95% CI: 1.9/1.2-3.3), and the coexistence of further bleeding defects (odds/95% CI: 1.8/1.03-3.1) partially account for the differences in the clinical bleeding phenotype associated with FVII deficiency.ConclusionThe clinical phenotype in individuals with FVII deficiency is impacted by factors such as age, blood group, and the concurrent presence of other bleeding defects.
| S-EPMC10779797 | biostudies-literature
Project description:Tissue factor (TF) pathway inhibitor (TFPI) is a Kunitz-type anticoagulation protein that inhibits activated factor VII (FVIIa)/TF complex. Incidentally, many different F7 gene variants, including TFPI-binding exosite mutations, have been reported in patients with congenital FVII deficiency and clinical bleeding variabilities. Here, TFPI-binding exosites (R147 and K192) on FVII zymogen were selectively disrupted to understand their roles in the pathogenesis of bleeding phenotypes. Expression of recombinant FVII variants (R147A, K192A, and R147A/K192A) demonstrated markedly reduced secretion of FVII owing to intracellular retention in the endoplasmic reticulum, as demonstrated by upregulation of the unfolded protein response genes in all FVII variants. FVII variants showed a similar FVII activation pattern and FVIIa amidolytic activity than FVII wild-type (WT). In contrast to FVII activation, R147A and K192A showed a 90% reduction in FX activation relative to WT, whereas the R147A/K192A variant demonstrated a 99% decrease in FX activation. The clotting time was markedly prolonged with R147A and K192A than WT, and no FVII coagulant activity was detected in R147A/K192A. In addition, the thrombin generation assay revealed a significant prolongation of lag time in all FVII variants. Our study explains how mutations of TFPI-binding exosites of FVII can lead to bleeding phenotypes in individuals carrying these aberrancies.
| S-EPMC9661381 | biostudies-literature
Project description: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.
| S-EPMC10889322 | biostudies-literature