F7 gene variants modulate protein levels in a large cohort of patients with factor VII deficiency

Abstract

Congenital factor VII (FVII) deficiency is a rare bleeding disorder caused by mutations in F7 gene with autosomal recessive inheritance. A clinical heterogeneity with poor correlation with FVII:C levels has been described. It was the objective of this study to identify genetic defects and to evaluate their relationships with phenotype in a large cohort of patients with FVII:C<50 %. One hundred twenty-three probands were genotyped for F7 mutations and three polymorphic variants and classified according to recently published clinical scores. Forty out of 123 patients (33 %) were symptomatic (43 bleedings). A severe bleeding tendency was observed only in patients with FVII:C<0.10 %. Epistaxis (11 %) and menorrhagia (32 % of females in fertile age) were the most frequent bleedings. Molecular analysis detected 48 mutations, 20 not reported in the F7 international databases. Most mutations (62 %) were missense, large deletions were 6.2 %. Compound heterozygotes/homozygotes for mutations presented lower FVII:C levels compared to the other classes (Chi=43.709, p<0,001). The polymorphisms distribution was significantly different among the three F7 genotypic groups (Chi=72.289, p<0,001). The presence of truncating mutations was associated with lowest FVII:C levels (Chi=21.351, p=0.002). This study confirms the clinical and molecular variability of the disease and the type of symptoms. It shows a good correlation between the type of F7 mutation and/or polymorphisms and FVII:C levels, without a direct link between FVII:C and bleeding tendency. The results suggest that large deletions are underestimated and that they represent a common mechanism of F7 gene inactivation which should always be investigated in the diagnostic testing for FVII deficiency.

In�vitro expression of mutant factor VII proteins and characterization of their clinical significance

“…Mutations in this domain may severely affect the coagulation activity and the secretion of the FVII protein. However, considerable evidence now supports the concept that there is no clear genotype-phenotype association in FVII deficiency (14). Preceded by several publications based on various mutations, it has been demonstrated that the disease manifestations, including epistaxis, hemarthrosis and menorrhagia, do not always associate with FVII:C (1,15).…”

Molecular Diagnosis of Inherited Coagulation and Bleeding Disorders

“…In these cases, intronic variants and epigenetic alterations can play a role in disease pathogenesis, and HTS may be relevant in these cases. 71 The most important findings derived from the molecular data from this study were: (1) patients with at least one variant involving a domain other than the catalytic domain of FVII presented Fig. 4 Genetic variants in the landscape of CalDAG-GEFI: the figures identify the many genetic variants that have been reported in CalDAG-GEFI that impair the function of these proteins and subsequently impair αIIbβ3 activation.…”

“…This detected several novel variants, and large deletions (6%), which are rarely reported in F7. 71 An underlying genetic variant was not found in 42% of the patients included. In these cases, intronic variants and epigenetic alterations can play a role in disease pathogenesis, and HTS may be relevant in these cases.…”

“…Variants are color-coded: yellow, Canault et al 63 ; red, Lozano et al 64 ; green, Sevivas et al 65 ; rose, Bermejo et al 66 ; blue, Kato et al 67 ; black, Westbury et al 68 more severe bleeding and (2) not only compound heterozygotes/homozygotes variants contribute to lower FVII levels compared with heterozygous variants, but also the presence of truncating variants (those which are expected to have profound impacts on gene function) were associated to severe bleeding phenotype. 71,72 Genotype-phenotype correlation is also clear in congenital fibrinogen disorders. 73 Casini et al showed that genotype provides fundamental information regarding the mechanism of the disease and may be useful for the classification of fibrinogen disorders, especially in case of severe hypofibrinogenemia and dysfibrinogenemia.…”

Factor VII Gene Defects: Review of Functional Studies and Their Clinical Implications

“…Furthermore, the affected women often suffer from severe menorrhagia [29] . In sum, FVII deficiency is a rare bleeding disorder with variable clinical symptoms [28][29][30][31][32][33][34][35][36][37] . However, in many cases, there is no direct correlation between the factor plasma levels and the severity of the disease symptoms [28][29][30]32,38] .…”