2026 Volume 63 Issue 2 Pages 115-124
Congenital platelet disorders (CPDs) encompass a diverse range of conditions characterized by diminished platelet count or function, which arise from pathogenic variants in genes that regulate megakaryocyte differentiation and thrombopoiesis. Despite the identification of numerous causative genes, diagnostic accuracy remains suboptimal, frequently leading to misdiagnoses, such as immune thrombocytopenia, and resulting in inappropriate treatment strategies. To address these challenges, we established a centralized diagnostic platform that integrates immunofluorescence, flow cytometry, and targeted high-throughput sequencing of 56 CPD-related genes, along with a nationwide registry. This comprehensive approach enabled the identification of pathogenic variants in approximately half of the enrolled patients, facilitating the diagnosis of a wide array of inherited platelet disorders. The registry also uncovered a marked diagnostic delay in cases of MYH9-related disease and provided valuable insights into the natural history of severe cases. In addition, in cases of ANKRD26-related thrombocytopenia, we investigated the association between ANKRD26 transcript levels and clinical manifestations. We also examined the relationship between GPIb expression and bleeding phenotype in patients with 22q11.2 deletion syndrome. Our genetic analysis also identified cases in which multiple causative genes contributed to congenital thrombocytopenia. Therefore, in situations where family history is complicated or clinical manifestations do not fully align with a single-gene disorder, it is imperative to consider the possibility of coexisting pathogenic variants. These findings highlight the importance of a nationwide diagnostic framework that combines morphologic, functional, and genetic analyses. Such an approach is vital for achieving early and accurate diagnosis, avoiding inappropriate therapies directed toward immune thrombocytopenia, and enhancing risk-adapted clinical management for patients with inherited platelet disorders.
