Identification of novel PROS1 variants through systematic analysis of patients with suspected hereditary protein S...

Protein S (PS) is an important, nonenzymatic cofactor with clinical relevance in coagulation disorders. Hereditary deficiency of PS is caused by pathogenic variants in the PROS1 gene, which encodes this protein. Identifying the presence and assessing the pathogenicity of PROS1 variants is essential for the effective management of patients with hereditary PS deficiency.

The aim of this study was to identify PROS1 variants in patients with suspected hereditary PS deficiency and to evaluate their pathogenicity.

The PROS1 coding sequence, including adjacent intron-exon boundaries, was analyzed in 276 patients with suspected hereditary PS deficiency using next-generation sequencing. Identified variants were evaluated based on existing literature, when available, or using bioinformatic prediction tools. The predicted pathogenicity was then compared with the patients' PS activity levels.

Forty-eight distinct variants were identified in 101 patients. Twenty-seven of these variants have been previously described in the literature, and their pathogenicity was categorized based on all available evidence. Of the remaining 21 variants, 11 are listed in ClinVar and/or dbSNP; 10 are novel. The potential pathogenicity of these variants, as well as possible explanations for PS deficiency in patients without an identified variant, are discussed.

In silico prediction tools are useful for a first assessment of pathogenicity for novel PROS1 variants. For a final evaluation of whether a variant is causative for hereditary PS deficiency, a comprehensive characterization is indispensable.