Quintavalle Gabriele, Riccardi Federica, Rivolta Gianna Franca, Martorana Davide, Di Perna Caterina, Percesepe Antonio, Tagliaferri Annarita
Gabriele Quintavalle, Regional Reference Centre for inherited bleeding disorders, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy, Tel.: +39 0521 703971, Fax: +39 0521 704332, E-mail:
Thromb Haemost. 2017 Aug 1;117(8):1455-1464. doi: 10.1160/TH17-02-0085. Epub 2017 Apr 27.
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.
先天性凝血因子VII（FVII）缺乏症是一种罕见的出血性疾病，由F7基因突变引起，呈常染色体隐性遗传。该病存在临床异质性，且与FVII：C水平相关性较差。本研究的目的是在一大群FVII：C<50%的患者中识别基因缺陷，并评估其与表型的关系。对123名先证者进行F7突变和三个多态性变体的基因分型，并根据最近发表的临床评分进行分类。123名患者中有40名（33%）出现症状（43次出血）。仅在FVII：C<0.10%的患者中观察到严重出血倾向。鼻出血（11%）和月经过多（育龄期女性的32%）是最常见的出血情况。分子分析检测到48种突变，其中20种未在F7国际数据库中报道。大多数突变（62%）为错义突变，大片段缺失占6.2%。与其他类型相比，突变的复合杂合子/纯合子的FVII：C水平较低（卡方=43.709，p<0.001）。三个F7基因型组之间的多态性分布存在显著差异（卡方=72.289，p<0.001）。截短突变的存在与最低的FVII：C水平相关（卡方=21.351，p=0.002）。本研究证实了该疾病的临床和分子变异性以及症状类型。它表明F7突变和/或多态性类型与FVII：C水平之间存在良好的相关性，而FVII：C与出血倾向之间没有直接联系。结果表明大片段缺失被低估了，它们代表了F7基因失活的一种常见机制，在FVII缺乏症的诊断检测中应始终进行调查。
