凝血因子Ⅸ基因新发错义突变致乙型血友病一例家系分析

Clinical Phenotype and Genetic Analysis of a Hemophilia B Family Caused by a Novel Missense Mutation of Coagulation Factor Gene

目的:分析一例乙型血友病(HemophiliaB,HB)家系的遗传学病因。方法:采用凝固法检测先证者及其家系成员凝血酶原时间(PT)、活化部分凝血酶时间(APTT)、凝血酶时间(TT),免疫比浊法检测D-二聚体浓度;采用血液分析仪检测血红蛋白(Hb)含量,发色底物法检测凝血因子Ⅸ(F9)活性,采用PCR-Sanger测序法分析HB的关键致病基因F9基因序列并进行突变分析。结果:先证者Hb含量降低,凝血功能示APTT延长,D-二聚体增高,F9活性明显下降;先证者母亲及女儿APTT及F9活性分别有不同程度的延长和降低,其父亲、妹妹和哥哥的APTT及F9活性正常。测序结果显示该家系先证者携带F9基因半合子错义突变c.289T>G(p.Cys97Gly),为首次发现的变异位点,先证者母亲及女儿各携带杂合突变。结论:F9基因第4外显子c.289T>G(p.Cys97Gly)半合子变异可能为HB致病性变异。

Objective:To analyze the F9gene mutation in a Hemophilia B(HB)of Hubei province,and to explore the relationship between genotype and phenotype.Method:Coagulation parameters of the family members were detected with coagulation indicators,including PT,APTT,TT,D-Dimer,etc.The F8and F9gene activity was detected by substrate method.The 8exons of F9gene and their flanking sequence of HB family members were detected with PCR amplification and direct sequencing.The data obtained were compared with data in the international F9gene mutations database.Results:The hemoglobin levels of the proband was decreased.The blood coagulation function test showed that the APTT was prolonged,the D-dimer was increased,and the F9activity was decreased significantly.While,the APTT and F9activity of the mother and daughter were prolonged and decreased in different degrees.The coagulation parameters of the other family members showed no obvious abnormalities.The sequencing results showed that the proband had a F9gene hemizygous missense mutation c.289T>G(p.Cys97Gly),which was the first time detected.The proband mother and daughter each carried a heterozygous mutation.Conclusion:The blood coagulation function test and clinical symptoms of the proband and the family members support c.289T>G mutation as a pathogenic mutation.