Cerebral venous sinus thrombosis in a family with protein S deficiency: genetic analysis and phenotypic characterization.

Abstract

Background: Protein S deficiency (PSD) markedly increases cerebral venous sinus thrombosis (CVST) risk; although global PROS1 variant data are extensive, Chinese reports remain limited.

Objective: To characterize the genetic and clinical phenotypes of a family with hereditary PSD presenting as CVST, and to preliminarily explore underlying molecular pathogenesis.

Methods: Clinical and coagulation data were collected from the proband and family members. CVST was confirmed by magnetic resonance venography (MRV). The coding region of PROS1 gene was sequenced, and the pathogenicity, evolutionary conservation, and functional impact of identified variant was evaluated using bioinformatics tools and Pymol software. The thrombin generation assay (TGA) was used to preliminarily assess the proband's thrombin generation capacity.

Results: The proband exhibited reduced PS activity (PS: A, 59%), along with decreased total and free PS antigen levels. Similar reductions were observed in her father, two sisters, and two nephews. MRV revealed extensive CVST. Genetic sequencing identified a heterozygous missense variant c.886 A > C (p.Lys296Gln) in exon 9 of the PROS1 gene in all affected individuals. The variant was classified as variant of uncertain significance. It resides in highly conserved region, altering local hydrophilicity and hydrogen bond interactions and likely impairing PS function. The TGA results indicated that the proband's thrombin generation capacity was significantly increased.

Conclusion: This study reports a PROS1-related CVST case in which inherited variant acted synergistically with modifiable prothrombotic risk factors. The findings underscore the importance of comprehensive etiological screening in unexplained thrombosis and support familial genetic counseling and surveillance for early prevention.