Pedigree analysis of cerebral venous sinus thrombosis associated with compound heterozygous hereditary protein S...

This study investigates the relationship between hereditary protein S deficiency (PSD) and cerebral venous sinus thrombosis (CVST) through phenotypic and genetic analyses in a proband and family members with compound heterozygous PROS1 mutations. A retrospective analysis was conducted on the clinical data of one patient diagnosed with CVST treated in The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University in July 2025. Peripheral venous blood samples were collected from the proband and 14 individuals from three generations, and relevant coagulation parameters and thrombin generation and inhibition assays were performed. Plasma protein S activity (PS: A), total protein S antigen (TPS: Ag), and free protein S antigen (FPS: Ag) were quantified. All exons and flanking regions of PROS1 were amplified by polymerase chain reaction (PCR) and analyzed by Sanger sequencing. Bioinformatics tools were used to evaluate mutation conservation, predict pathogenicity, and analyze structural effects on the protein. Thrombin generation and inhibition assays indicated defective anticoagulant function in the proband. The proband was diagnosed with CVST and type Ⅰ PSD (PS: A 39%, TPS: Ag 53 mg/L, FPS: Ag 42 mg/L). Genetic analysis identified a heterozygous missense variant c.1544G > A (p.Arg515His) and a heterozygous synonymous mutation c.2001 A > G (p.Pro667Pro) in the PROS1 gene. Arg515 was highly conserved across nine homologous species. The p.Arg515His mutation was predicted to be pathogenic and associated with reduced protein stability and abnormal folding. Compound heterozygous variants c.1544G > A and c.2001 A > G in the PROS1 gene may be associated with reduced protein S levels in this pedigree. The occurrence of CVST in the proband with PSD patients may also be related to these compound heterozygous variants.