遗传性蛋白S缺乏症18例临床表现与基因分析

Clinical manifestations and gene analysis of 18 cases of hereditary protein S deficiency

目的分析18例遗传性蛋白S(PS)缺乏症患者的临床表现及分子致病机制。方法对2016年7月至2019年2月就诊于中国医学科学院血液病医院的18例PS缺乏症患者进行回顾性分析,应用凝固法测定PS活性、应用发色底物法测定蛋白C(PC)和抗凝血酶(AT)活性并进行初步诊断,使用高通量测序(HTS)筛查凝血疾病相关基因变异并进行Sanger测序验证;使用Swiss-model软件进行三维结构分析。结果18例患者中男15例,女3例,中位年龄37(14~62)岁。均有深静脉血栓栓塞病史,PS活性为12.5~48.2 U/dl。所有患者均检出PROS1基因变异,其中5个无义突变(c.134;62del/p.Leu45*、c.847G>T/p.Glu283*、c.995;96delAT/p.Tyr332*、c.1359G>A/p.Trp453*、c.1474C>T/p.Gln492*)、2个移码突变(c.1460delG/p.Gla487Valfs*9、c.1747;750delAATC/p.Asn583Wfs*9)和1个大片段缺失(外显子9缺失)为首次报道。此外,1例妊娠期深静脉血栓形成女性患者的PS活性为55.2 U/dl,并且检出PROC基因c.565C>T/p.Arg189Trp突变。结论该研究新发现的基因突变丰富了与遗传性PS缺乏症相关的PROS1基因突变谱。

Objective To analyze the clinical manifestations and molecular pathogenesis of 18 patients with inherited protein S(PS)deficiency.Methods Eighteen patients with inherited PS deficiency who were admitted to the Institute of Hematology&Blood Diseases Hospital from June 2016 to February 2019 were analyzed:activity of protein C(PC)and antithrombin(AT),PS activity were measured for phenotype diagnosis;high throughput sequencing(HTS)was used for screening of coagulation disease-related genes;Sanger sequencing was used to confirm candidate variants;Swiss-model was used for three-dimensional structure analysis.Results The PS:C of 18 patients ranged from 12.5 to 48.2 U/dL.Among them,16 cases developed deep vein thrombosis,including 2 cases each with mesenteric vein thrombosis and cerebral infarction,and 1 case each with pulmonary embolism and deep vein thrombosis during pregnancy.A total of 16 PROS1 gene mutations were detected,and 5 nonsense mutations(c.134_162del/p.Leu45*,c.847G>T/p.Glu283*,c.995_996delAT/p.Tyr332*,c.1359G>A/p.Trp453*,c.1474C>T/p.Gln492*),2 frameshift mutations(c.1460delG/p.Gla487Valfs*9 and c.1747_1750delAATC/p.Asn583Wfs*9)and 1 large fragment deletion(exon9 deletion)were reported for the first time.In addition,the PS:C of the deep vein thrombosis during pregnancy case was 55.2 U/dL carrying PROC gene c.565C>T/p.Arg189Trp mutation.Conclusion The newly discovered gene mutations enriched the PROS1 gene mutation spectrum which associated with inherited PS deficiency.