Application of multigene panel testing for bleeding, thrombotic, and platelet disorders in patients and the general population in China

Bleeding, thrombotic, and platelet disorders (BTPDs) are rare but complex conditions with diverse clinical presentations that often delay accurate diagnosis. In this study, we developed an Expanded Thrombohemostasis (ExTH) gene panel comprising 130 diagnostic and risk-associated genes. This panel was applied to 747 patients and 760 controls, representing the largest genetic screening study for BTPDs in an Asian population to date. A high overall diagnostic yield of 54.8% was achieved, with mutation carriers exhibiting more severe clinical phenotypes. Notably, the diagnostic rate was significantly higher in younger individuals, underscoring the clinical value of early genetic screening. Beyond traditional Tier 1 gene panels, we identified disease-causing variants in unexpected categories in 4.28% of patients, revealing extensive genotype-phenotype overlap and advocating for a broader diagnostic approach. Some pathogenic variants exhibited normal results in conventional coagulation assays, highlighting the limitations of standard functional testing in detecting underlying genetic causes. These findings establish the ExTH gene panel as a powerful tool for comprehensive genetic diagnosis, capable of capturing clinically relevant variants that would be missed by conventional approaches. This study provides new insight into the molecular landscape of BTPDs, and supports the integration of broad gene panel testing into routine clinical workflows to improve diagnostic accuracy, risk stratification, and personalized treatment.