What does this research mean for the field?

The heterozygous missense variant c.886 A > C (p.Lys296Gln) in the PROS1 gene impairs protein S function and contributes to hereditary protein S deficiency and cerebral venous sinus thrombosis. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

To explore the genetic and clinical characteristics of a family with hereditary protein S deficiency manifesting as cerebral venous sinus thrombosis.

June 27, 2026Open Access

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

Key Points

To explore the genetic and clinical characteristics of a family with hereditary protein S deficiency manifesting as cerebral venous sinus thrombosis.
Clinical and coagulation data collected from the proband and family members.
Magnetic resonance venography confirmed cerebral venous sinus thrombosis.
Genetic sequencing of the PROS1 gene and functional impact assessment using bioinformatics tools.
The proband exhibited significant reductions in protein S activity and antigen levels (PS: A, 59%).
A heterozygous missense variant c.886 A > C (p.Lys296Gln) was identified in all affected family members.
Thrombin generation assays showed significantly increased thrombin generation capacity in the proband.

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.

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