Molecular genetic analysis of congenital thrombocytopenia, hemostatic and coagulation disorder

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17865
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Yokohama City University
• Principal Investigator: UCHIYAMA Yuri 横浜市立大学, 附属病院, 助教 (50829794)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 先天性造血器障害 / 汎血球減少症 / 血小板減少症 / 全エクソーム解析

Outline of Final Research Achievements

Thrombocytopenia occurring in childhood must be differentiated from immune thrombocytopenia, hematological malignancy, bone marrow failure, and inherited thrombocytopenia.
In this study, exome sequencing identified gene A and B in two families with pancytopenia and congenital thrombocytopenia, respectively. The pathogenicity of these two genes and variants were subsequently evaluated by deep-sequencing, RT-PCR, and/or RNA-sequencing. Deep-sequencing results was strongly convinced that this variant was derived from the early-phase somatic mosaicism. However, lymphoblastoid cell lines derived from patient’s blood could not include the cells with the variant. The strong toxicity of the variant of gene A induced cell mortality. A total of 42 families of congenital abnormalities of thrombosis and/or hemostasis was performed for exome sequencing. The diagnostic rate was 23.8% (10/42). Exome sequencing is useful technique for the rare disorder associated with congenital thrombocytopenia.

Free Research Field

先天性止血凝固異常

Academic Significance and Societal Importance of the Research Achievements

先天性血小板減少症の遺伝的原因を明らかにすることで、疾患の背景を明らかにすることができる。造血の過程のどの段階での異常かを同定することは、先天性造血障害における治療方針を検討する上で大きな指針の一つとなるため、新規疾患の遺伝的原因の解明は非常に重要である。これら先天性疾患の遺伝的疾患原因解明は、後天性疾患である多くの造血不全・造血器腫瘍の理解・治療につながることが期待される。
患者抽出方法を含め、本手法を用いた先天性血小板減少症・止血凝固異常症の遺伝的疾患病態の解明は、非常に効率的であることが示された。