Novel insights into inherited protein C deficiency from an interactive PROC variant database.

Abstract

Background: Hundreds of PROC variants have been identified that cause inherited PROC deficiency (PCD), which increases the risk of thrombosis and other complications, however, it is not well studied for inherited PCD globally.

Objectives: To build an interactive PROC variant database for conveniently communicating, and to systematically study the epidemiology, genotype-phenotype relationships, and pathogenesis of inherited PCD.

Methods: An interactive PROC variant database was built by collecting the inherited PCD data from literature. Statistical analysis was performed for the epidemiology, clinical characteristics, genotype-phenotype's relationship, risk assessment and pathogenesis of inherited PCD.

Results: In the database, 3995 entries, including 242 individuals with biallelic variations (BVs) and 3753 individuals with monoallelic variations (MVs), were collected and 506 unique variations were identified. Some hotspot variations exhibited ethnic specificity and different prevalence. The spectrums of clinical presentations and the first onset age were different between individuals with BVs and MVs. Besides thrombotic related symptoms, a few nonthrombotic symptoms, including miscarriage in individuals with MVs, bleeding disorder, ocular disorder and hypertension in BV individuals, should not be overlooked. The PROC activity was linearly related to the first onset age in BV individuals, but not MV individuals. There might be other thrombophilia factors to trigger thrombosis for MV individuals. Additionally, missense variations in different PROC's subdomains should have different pathogenesis.

Conclusion: The database was convenient to retrieve pathogenic variants and clinical presentations, and useful to understand clinical heterogeneity of inherited PCD and pathogenic risk of the variations, which should benefit the diagnosis and management of inherited PCD patients.