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

• DOI: 10.1038/s42003-025-07935-x
• Publication Date: 2025-04-12T07:20:37Z
• Authors: Zhu Zhang; Haobo Li; Zhaoman Wan; Mingming Su; Yu Zhang; Tao Yang; Xiaofan Ji; Jianlong Men; Guoqiang Xing; Jing Han; Yingqun Ji; Wei Zhang; Hong Chen; Xiaomao Xu; Jianwen Fei; Chunling Dong; Yuanhua Yang; Yan Wu; Qun Yi; Wenyi Pang; Meng Zhang; Chong Shi; Kaiyuan Zhen; Dingyi Wang; Jieping Lei; Sinan Wu; Shi Shu; Yunxia Zhang; Shuai Zhang; Qian Gao; Jun Wan; Wanmu Xie; Peiran Yang; Peng Zhang; Xianbo Zuo; Taijiao Jiang; Zhenguo Zhai; Chen Wang

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