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F7 gene variants modulate protein levels in a large cohort of patients with factor VII deficiency. Results from a genotype-phenotype study.

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 (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.

journal_name

Thromb Haemost

journal_title

Thrombosis and haemostasis

authors

Quintavalle G,Riccardi F,Rivolta GF,Martorana D,Di Perna C,Percesepe A,Tagliaferri A,Ad-Hoc Study Group.

doi

10.1160/TH17-02-0085

subject

Has Abstract

pub_date

2017-08-01 00:00:00

pages

1455-1464

issue

eissn

0340-6245

issn

2567-689X

pii

17-02-0085

journal_volume

117

pub_type

杂志文章,多中心研究

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F7 gene variants modulate protein levels in a large cohort of patients with factor VII deficiency. Results from a genotype-phenotype study.