OBJECTIVE: To explore the molecular pathogenesis of a Chinese pedigree affected with inherited protein C (PC) deficiency. METHODS: The protein C activity (PC:A) and protein C antigen (PC:Ag) of the proband and his family members were determined by a chromogenic substrate method and enzyme-linked immunosorbent assay, respectively. The proband was subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing of other members of the pedigree. RESULTS: The PC:A and PC:Ag of proband were reduced to 15% and 11%, respectively. The above parameters of his parents and elder sister were also decreased to approximately 50% of reference values. Next generation sequencing has revealed that the proband has harbored a heterozygous c.572_574delAGA (p.Glu191_Lys192delinsGlu) variant in exon 7 and a missense c.752C>T (p.Ala251Val) variant in exon 8 of the PROC gene. His father was heterozygous for the c.572_574delAGA variant, while his mother and elder sister were heterozygous for the c.752C>T variant. According to the American College of Medical Genetics and Genomics Standards and Guidelines, the c.572_574delAGA (p.Glu191_Lys192 delinsGlu) variant was predicted to be likely pathogenic (PS1+PM4+PP3). c.752 C>T (p.Ala251Val) variant was also likely pathogenic (PS1+PM1+PP3). CONCLUSION The deletional variant of c.572_574delAGA (p.Glu191_Lys192delinsGlu) in exon 7 and missense variant c.752C>T (p.Ala251Val) in exon 8 of the PROC gene probably underlay the inherited protein C (PC) deficiency in this pedigree. Above finding has enriched the spectrum of PROC gene variants and provided a basis for genetic counseling for this pedigree.
Humans ; China ; Mutation ; Pedigree ; Protein C/genetics* ; Protein C Deficiency/genetics* ; Male ; Female

Brain metastasis (BM) is a common complication in non-small cell lung cancer (NSCLC), which associates with poor prognosis. Recently, immune checkpoint inhibitors (ICIs) has revolutionized the treatment of tumors. Programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors could produce antitumor effect by activating the autoimmune system. The immunotherapy has already show to have a promising outcome for NSCLC patients with BM, while its specific curative effect and the most ideal mode of the treatment remain to be explored. Here we reviewed the tumor microenvironment (TME) in BM lesions and summarized the role of PD-1/PD-L1 inhibitors in cerebral and its current status in clinical studies.
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