Genetic and functional characterization of a novel SERPIND1 variant in a family with isolated gastric varices and venous thrombosis

Abstract Background Isolated gastric varices type I (IGV1) is a rare but severe manifestation of splenic vein thrombosis. While thrombophilia is a recognized cause, the underlying genetic determinants are often elusive. This study investigates the case of a proband presenting with IGV1, deep vein thrombosis (DVT), and Long QT syndrome Type 2 (LQT2), aiming to elucidate the genetic basis and functional impact of the identified SERPIND1 variants. Methods Whole-exome sequencing identified candidate variants in the proband, which were validated by Sanger sequencing. Functional assessment included quantifying SERPIND1 and KCNH2 mRNA in proband and control blood, analyzing heparin cofactor Ⅱ (HCⅡ) protein expression and localization in transfected 293T cells, and predicting the potential structural consequences of the variants using bioinformatic tools. Results The proband, a 31-year-old female, presented with isolated gastric fundal varices and a history of deep venous thrombosis (DVT), along with long QT syndrome type 2 (LQT2). Whole-exome sequencing (WES) identified two heterozygous variants, both confirmed by Sanger sequencing: a de novo SERPIND1 c.940 C > T (p.Arg314Trp) variant, classified as Pathogenic according to ACMG guidelines (PS2, PS3, PM2_Supporting, PP3), and a KCNH2 c.1707 C > A (p.Tyr569*) variant, also classified as Pathogenic (PVS1, PP1, PM2_Supporting) and showing familial co-segregation. The SERPIND1 variant was associated with reduced HCⅡ antigen levels and activity in plasma. In vitro assays revealed that both variants led to significantly reduced SERPIND1 and KCNH2 mRNA expression. In transfected cells, the SERPIND1 p.Arg314Trp variant markedly decreased HCⅡ protein levels and possibly induced aberrant nuclear mislocalization. Structural modeling suggested that the Arg314Trp substitution disrupts a key hydrogen bond within HCⅡ, while the KCNH2 p.Tyr569* nonsense variant is predicted to generate a truncated protein. Conclusion The SERPIND1 c.940 C > T (p.Arg314Trp) variant is associated with reduced HCⅡ expression and functional impairment, which may contribute to a prothrombotic tendency in this patient. This study provides a hypothesis-generating observation supporting a potential role of HCⅡ deficiency in venous thrombosis and IGV1. The KCNH2 variant was accounted for the coexisting LQT2 phenotype.