New diagnostic system, registry, and sample bank for congenital thrombocytopenia in Japan

Abstract

Congenital thrombocytopenia (CT) is a heterogeneous group of bleeding disorders caused by inherited defects in platelet production. Recent studies have elucidated several causative genes for the disorders; however, the major causes remain unknown. Although CT has been considered rare, about 10% of cases of chronic/intractable immune thrombocytopenia (ITP) should be diagnosed as CT. Platelet transfusion is contraindicated for ITP, but remains a key option for CT. Once ITP is diagnosed, patients with CT are often treated with glucocorticoids and by splenectomy. In addition, patients with MYH9 disorders often develop nephritis and deafness. Cases with defects in transcription factors may be associated with hematological malignancy. There is a pressing need for the development of an operational system for the differential diagnosis of CT. To solve this issue, we developed a new system, based on an AMED grant that aims to (1) establish a centralized diagnosis system using conventional immunofluorescence staining, flow cytometry, and next-generation sequencing panel analysis using 56 known pathogenic genes, (2) perform whole-exome sequencing analysis in families without any known pathogenic variants in the panel analysis, (3) archive samples at the National Center for Child Health and Development (NCCHD), and (4) establish a nationwide registry for CT at the NCCHD. We have registered 137 cases and analyzed 120 cases, which led to the identification of pathogenic variants of MYH9, WAS, VWF, ITGA2B, ITGB3, ETV6, RUNX1, ANKRD26, ACTN1, CDC42, and FLNA. The novel system will contribute to the investigational and clinical development of CT in Japan.