目的 探讨9个遗传性凝血因子Ⅶ( coagulation factorⅦ,FⅦ)缺陷症家系的基因突变类型与临床特征.方法 检测凝血酶原时间、活化部分凝血活酶时间及FⅦ活性和抗原等指标以明确诊断;用PCR法扩增先证者F7基因的全部外显子及侧翼序列、5′和3′非翻译区.PCR产物纯化后直接测序,寻找基因突变,用反向测序证实所发生的突变.结果 9个家系中的先证者凝血酶原时间均延长,FⅦ活性在2.0％～6.0％之间,7例先证者的FⅦ抗原显著减低.共发现8种F7基因突变,其中g.8355 A＞T(Gln100Leu)、g.11243T＞C(Ser269Pro)和g.11520_11521insT 3种突变为首次发现;6种突变发生在催化区;缺失突变和插入突变各1种,其余均为错义突变;所有的基因突变均来自先证者的父亲和(或)母亲,发现5个家系存在近亲婚配.g.27_28delCT、Cys329Gly、Arg304Trp和His348Gln突变在无亲缘关系的家系中重复出现.不同基因突变类型的临床表型有较大差异:2例His348Gln及1例Arg304Trp纯合突变可表现为轻型和无症状,2例g.27_28delCT纯合、杂合突变分别表现为中型、无症状,4例双杂合突变分别表现为1例(Ser269Pro和Cys329Gly)无症状、2例(Arg304Trp和Cys329Gly与Arg277Cys和g.11520_11521insT)轻型、1例(Gln100Leu和His348Gln)中型.结论 中国汉族人群中存在导致F7基因缺陷的突变热点.遗传性凝血因子Ⅶ缺陷症患者的临床表型与FⅦ活性、F7基因突变类型无明显的相关性.%Objective To investigate potential mutations and clinical features of 9 unrelated patients with inherited coagulation factor Ⅶ (FⅦ) deficiency.Methods Clinical diagnosis was validated by assaying of coagulation parameters including prothrombin time,activated partial thromboplastin time,FⅦ activity and specific antigens. All exons,exon-intron boundaries,and 5′ and 3′ untranslated regions of F7 genes were amplified with PCR.Potential mutations were detected by direct sequencing of purified PCR products.Suspected mutations were confirmed by sequencing of the opposite strand.Results All probands have featured prolonged prothrombin time,with FⅧ activity ranging between 2.0％ to 6.0％.The titers of FⅧ antigen were significantly reduced in 7 probands. Eight mutations,including 6 missense mutations,1 deletion and 1 insertion,were identified,among which 3 (Gln100Leu,Ser269Pro and g.11520_11521insT) were not described previously.Six mutations have located in the protease domain.All mutations were inherited,and consanguineous marriages were reported in 5 families.Mutations g.27_28delCT,Cys329Gly,Arg304Trp and His348Gln have been identified in unrelated families. There was a lack of correlation between the mutations and their clinical features.Two individual with homozygous His348Gln mutations and 1 individual with homozygous Arg304Trp mutation were only mildly affected or asyrnptomatic.Two patients,who have respectively carried homozygous and heterozygous deletions of g.27_ 28delCT,were moderately affected and asymptomatic.In 4 patients carrying double heterozygous mutations,1 (Ser269Pro and Cys329Gly) was asymptomatic,2 (Arg304Trp and Cys329Gly,Arg277Cys and g.11520_11521insT,respectively) had a mild bleeding tendency,whilst 1 (Gln100Leu and His348Gln) has a moderate bleeding diathesis.Conclusion There seem to be hotspots of F7 gene mutations in ethnic Han Chinese populations.And there is a lack of correlation between particular types of mutations and clinical phenotypes.
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