Whole genome sequencing identifies pathogenic genetic variants in Han Chinese patients with familial venous thromboembolism

Genetic factors play a pivotal role in determining venous thromboembolism (VTE) risk, particularly in cases of unprovoked early-onset VTE and those with a family history. While genome-wide association studies (GWAS) has advanced our understanding, high-quality whole-genome sequencing (WGS) from family-based studies is essential to elucidate the role of rare variants. In this study, we performed WGS on 216 individuals from 35 Han Chinese VTE pedigrees and validated findings in 99 high-heritability VTE cases using whole-exome sequencing. Functional impact was assessed via qPCR and Western Blot in HEK293T cells. Classical genes explained partial familial inheritance (20/35), while non-classical genes showed comparable effects on VTE recurrence and CTEPH. From 36 rare variants, 34 pedigrees (97%) were interpreted, with 29 variants reported for the first time. Notably, three novel variants, GP6 (c.G1094A:p.R365H), TET2 (c.G3451T:p.E1151X), and JAK2 (c.G380A:p.G127D), shared in two unrelated pedigrees each and are classified as low frequency in East Asians. Functional analyses revealed significant changes in GP6 and TET2 expression compared to the wild type. These findings provide novel insights into the genetic architecture of VTE and highlight GP6, TET2, and JAK2 as potential risk factors in East Asian populations, underscoring the clinical relevance of rare variants in VTE pathogenesis.

Authors

Institutions

Publication Details

Journal
Communications Biology
Published
2025-04-12
DOI
https://doi.org/10.1038/s42003-025-07935-x
Citations
10
Primary Topic
Venous Thromboembolism Diagnosis and Management
Type
article
Field-Weighted Citation Impact
18.70

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Whole genome sequencing identifies pathogenic genetic variants in Han Chinese patients with familial venous thromboembolism

Jieping Lei, Wei Zhang, Chunling Dong, Zhenguo Zhai et al.
10 citations
Communications Biology
Venous Thromboembolism Diagnosis and Management
18.70
article

Whole genome sequencing identifies pathogenic genetic variants in Han Chinese patients with familial venous thromboembolism

Jieping Lei, Wei Zhang, Chunling Dong, Zhenguo Zhai, Kaiyuan Zhen, Sinan Wu, Yingqun Ji, Jianwen Fei, Mingming Su, Qun Yi, Shuai Zhang, Peiran B Yang, Xiaofan Ji, Tao Yang, Yuanhua Yang, Chong Shi, Shi Shu, Hong Chen, Peng Zhang, Zhu Zhang, Haobo Li, Yunxia Zhang, Dingyi Wang, Qian Gao, Xianbo Zuo, Yan Wu, Jun Wan, Guoqiang Xing, Jing Han, Taijiao Jiang, Meng Zhang, Zhaoman Wan, Yu Zhang, Wanmu Xie, Wenyi Pang, Jianlong Men, Xiaomao Xu, Chen Wang
article en
10 citations

Abstract

Genetic factors play a pivotal role in determining venous thromboembolism (VTE) risk, particularly in cases of unprovoked early-onset VTE and those with a family history. While genome-wide association studies (GWAS) has advanced our understanding, high-quality whole-genome sequencing (WGS) from family-based studies is essential to elucidate the role of rare variants. In this study, we performed WGS on 216 individuals from 35 Han Chinese VTE pedigrees and validated findings in 99 high-heritability VTE cases using whole-exome sequencing. Functional impact was assessed via qPCR and Western Blot in HEK293T cells. Classical genes explained partial familial inheritance (20/35), while non-classical genes showed comparable effects on VTE recurrence and CTEPH. From 36 rare variants, 34 pedigrees (97%) were interpreted, with 29 variants reported for the first time. Notably, three novel variants, GP6 (c.G1094A:p.R365H), TET2 (c.G3451T:p.E1151X), and JAK2 (c.G380A:p.G127D), shared in two unrelated pedigrees each and are classified as low frequency in East Asians. Functional analyses revealed significant changes in GP6 and TET2 expression compared to the wild type. These findings provide novel insights into the genetic architecture of VTE and highlight GP6, TET2, and JAK2 as potential risk factors in East Asian populations, underscoring the clinical relevance of rare variants in VTE pathogenesis.

Communications BiologyVol. 8(1)
Second Military Medical University (CN), Capital Medical University (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Peking University (CN), Sichuan University (CN), Beijing Chao-Yang Hospital, Capital Medical University (CN), China-Japan Friendship Hospital (CN), Peking Union Medical College Hospital (CN), Tianjin Medical University General Hospital (CN), Beijing Jishuitan Hospital (CN), West China Hospital of Sichuan University (CN), First Affiliated Hospital of Guangzhou Medical University (CN), Guangzhou Chemistry (China) (CN), Beijing Anzhen Hospital (CN), Beijing Hospital (CN), Suzhou Institute of Systems Medicine (CN), Shanghai East Hospital (CN), The Affiliated Yongchuan Hospital of Chongqing Medical University (CN), Second Affiliated Hospital of Jilin University (CN), Yantaishan Hospital (CN), Beijing Children’s Hospital (CN), Beijing Friendship Hospital (CN), Central Hospital of Zibo (CN), Guizhou Provincial People's Hospital (CN), State Key Laboratory of Respiratory Disease (CN), Wuxi People's Hospital (CN), Shanxi Academy of Medical Sciences (CN), Chongqing Medical University (CN), Guangzhou Medical University (CN)
National Natural Science Foundation of China, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing Nova Program, Bijzonder Onderzoeksfonds UGent, National Key Research and Development Program of China
Zero hunger
Openalex Percentile: Top 0%
Venous Thromboembolism Diagnosis and Management
18.70
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.