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.