Genetic and functional characterization of a novel SERPIND1 variant in a family with isolated gastric varices and venous thrombosis.
8 affiliations
- 1Department of Gastroenterology and Hepatology and Traditional Chinese Medicine and Nephrology, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, No. 134, Dongjie, Fuzhou, 350001, China.
- 2Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou University, Fuzhou, China.
- 3Department of Gastroenterology and Hepatology and Traditional Chinese Medicine and Nephrology, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, No. 134, Dongjie, Fuzhou, 350001, China. [email protected].
- 4Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou University, Fuzhou, China. [email protected].
- 5Department of Gastroenterology and Hepatology and Traditional Chinese Medicine and Nephrology, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, No. 134, Dongjie, Fuzhou, 350001, China. [email protected].
- 6Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou University, Fuzhou, China. [email protected].
- 7Department of Gastroenterology and Hepatology and Traditional Chinese Medicine and Nephrology, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, No. 134, Dongjie, Fuzhou, 350001, China. [email protected].
- 8Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou University, Fuzhou, China. [email protected].
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.
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BibTeX
@article{lin2026genetic,
title = {{Genetic and functional characterization of a novel SERPIND1 variant in a family with isolated gastric varices and venous thrombosis.}},
author = {Xue-Yan Lin and Li-Jin Zhang and Jian-Hui Zhang and Ruo-Li Wang and Li-Fang Lin and Gui-Fang Huang and Dan-Dan Ruan and Zhi-Hai Zheng and Jie-Wei Luo and Ming-Hong Chen},
journal = {BMC gastroenterology},
year = {2026},
month = jul,
doi = {10.1186/s12876-026-05163-z},
url = {https://europepmc.org/article/MED/42897473},
note = {CC BY},
}
RIS
TY - JOUR
TI - Genetic and functional characterization of a novel SERPIND1 variant in a family with isolated gastric varices and venous thrombosis.
AU - Xue-Yan Lin
AU - Li-Jin Zhang
AU - Jian-Hui Zhang
AU - Ruo-Li Wang
AU - Li-Fang Lin
AU - Gui-Fang Huang
AU - Dan-Dan Ruan
AU - Zhi-Hai Zheng
AU - Jie-Wei Luo
AU - Ming-Hong Chen
PY - 2026
DA - 2026/07/01
JO - BMC gastroenterology
DO - 10.1186/s12876-026-05163-z
UR - https://europepmc.org/article/MED/42897473
AB - 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.
SN - 1471-230X
ER -