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

Gabriele Quintavalle; Federica Riccardi; Gianna Franca Rivolta; Davide Martorana; Caterina Di Perna; Antonio Percesepe; Annarita Tagliaferri; on behalf of the Ad-Hoc Study Group

doi:10.1160/TH17-02-0085

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2017; 117(08): 1455-1464
DOI: 10.1160/TH17-02-0085

Coagulation and Fibrinolysis

Schattauer GmbH

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

Results from a genotype-phenotype study

Gabriele Quintavalle

¹Regional Reference Centre for Inherited Bleeding Disorders, University Hospital of Parma, Parma, Italy

,

Federica Riccardi

¹Regional Reference Centre for Inherited Bleeding Disorders, University Hospital of Parma, Parma, Italy

,

Gianna Franca Rivolta

¹Regional Reference Centre for Inherited Bleeding Disorders, University Hospital of Parma, Parma, Italy

,

Davide Martorana

²Genetic Unit, University Hospital of Parma, Parma, Italy

,

Caterina Di Perna

¹Regional Reference Centre for Inherited Bleeding Disorders, University Hospital of Parma, Parma, Italy

,

Antonio Percesepe

²Genetic Unit, University Hospital of Parma, Parma, Italy

,

Annarita Tagliaferri

¹Regional Reference Centre for Inherited Bleeding Disorders, University Hospital of Parma, Parma, Italy

,

on behalf of the Ad-Hoc Study Group

› Institutsangaben

Abstract

Summary

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 (Chi²=43.709, p<0,001). The polymorphisms distribution was significantly different among the three F7 genotypic groups (Chi²=72.289, p<0,001). The presence of truncating mutations was associated with lowest FVII:C levels (Chi²=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.

Keywords

Bleeding score - factor VII deficiency - gene deletion - genotype - phenotype

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Referenzen

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