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Measurement of Factor V Activity in Human Plasma Using a Microplate Coagulation Assay
Published on: September 9, 2012
Genetic Landscape of Factor VII Deficiency: Insights from a Comprehensive Analysis of Pathogenic Variants and Their
Barbara Preisler1, Behnaz Pezeshkpoor1, Anja Merzenich1
1Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Faculty of Medicine, University Clinic Bonn, 53127 Bonn, Germany.
Insights
Genetic variants in the F7 gene cause factor VII (FVII) deficiency. A study found a 55% variant detection rate and identified the M2 allele as associated with reduced FVII activity, especially in mild cases.
Area of Science:
- Genetics
- Hematology
- Molecular Biology
Background:
- Congenital factor VII (FVII) deficiency is a rare inherited bleeding disorder.
- It results from genetic variations within the F7 gene, impacting coagulation FVII levels.
Purpose of the Study:
- To determine the pathogenic variant detection rate in the F7 gene for FVII deficiency.
- To explore genotype-phenotype correlations, specifically linking F7 genotype to FVII activity (FVII:C).
- To investigate the impact of the common M2 allele (rs6046: c.1238G>A; p.(Arg413Gln)) on FVII:C.
Main Methods:
- Genetic analysis of the F7 gene in 704 index patients using Sanger or next-generation sequencing.
- Calculation of variant detection rate (VDR) and correlation analysis with FVII:C levels.
- Assessment of the M2 allele frequency in relation to FVII deficiency severity and presence of pathogenic variants.
Main Results:
- A 55% variant detection rate (VDR) was achieved in 704 index patients.
- The VDR showed a negative correlation with increasing FVII:C levels.
- The M2 allele was more frequent in mild FVII deficiency and in patients without identified pathogenic variants, supporting its role in reducing FVII:C.
Conclusions:
- FVII:C levels can serve as a predictive marker for identifying pathogenic F7 variants in FVII deficiency.
- The M2 allele is associated with decreased FVII:C, particularly contributing to mild factor VII deficiency.
- This study enhances understanding of the genetic basis of FVII deficiency and genotype-phenotype relationships.
Abstract:
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.
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