遗传性蛋白S缺乏症18例临床表现与基因分析

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.