Phenotype–Genotype characterization of inherited Protein C deficiency in a qatari family Free

Background Protein C deficiency is an autosomal dominant thrombophilia caused by pathogenic variants in the PROC gene. Heterozygous deficiency affects approximately 1 in 200–500 individuals, with 3–5% of patients with VTE having protein C deficiency. Severe (homozygous or compound heterozygous) forms are rare and typically present in neonates with purpura fulminans and disseminated intravascular coagulation (DIC).

In heterozygous individuals, clinical expression is variable and influenced by environmental or additional genetic risk factors. Common manifestations include deep vein thrombosis (DVT) and pulmonary embolism (PE); less frequently, cerebral or mesenteric veins thrombosis.

Although protein C deficiency is globally recognized, data from the Middle East—particularly familial cases—remain limited. In regions with high consanguinity such as Qatar, the risk of homozygous mutations is elevated, underscoring the importance of molecular evaluation in extended families.Methods and Results We evaluated a multigenerational Qatari family referred for assessment of inherited thrombophilia. The proband, a 31-year-old female, was initially referred to hematology due to an extensive family history of venous thromboembolism (VTE). Laboratory investigations revealed reduced protein C activity (42% and 48%; reference range: 70–140%) with normal blood counts. She had no history of thrombosis or hemostatic challenges. Based on these findings, she was referred to the genetics department for further evaluation.

Single-gene sequencing of the PROC gene identified a heterozygous likely pathogenic variant: c.902C>T; p.(Ala301Val) (NM_000312.3), consistent with inherited protein C deficiency.

Family history includes multiple paternal relatives affected by VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE). A summary of affected individuals is presented in the family pedigree.

All four of the proband's siblings underwent protein C testing for the first time during this evaluation. Each was found to carry the same PROC variant, with protein C activity ranging from 47.7% to 59.3%. None have experienced symptoms or thrombotic events to date.Protein C testing and Genetic Analysis Protein C activity was quantitated using the Siemens Berichrom® Protein C kit which is a kinetic test that detects the amidolytically active portion of the activated protein C using a chromogenic substrate.

Genetic testing was conducted at a reference laboratory using bi-directional capillary sequencing. Targeted familial testing confirmed the presence of the PROC c.902C>T (p.Ala301Val) variant in all tested siblings. This variant—also known as A259V—has been previously reported in unrelated individuals with PROC-related thrombophilia and reduced protein C levels (PMID: 1678832) but has not been observed in the homozygous state in large population controls (gnomAD). In silico analysis supports a deleterious impact on protein structure and function.Conclusion The identification of this clinically significant PROC variant in a consanguineous Qatari family emphasizes the need for region-specific genomic data and local interpretation frameworks, as rare pathogenic alleles may be underrepresented in global databases. In high-consanguinity populations, targeted familial testing facilitates early identification of at-risk individuals, enabling timely implementation of preventive strategies such as perioperative and postpartum anticoagulation. With appropriate management, the life-threatening complications of protein C deficiency can be largely prevented.