CHARACTERIZATION OF A SERIES OF PATIENTS WITH GNE-RELATED THROMBOCYTOPENIA: INSIGHTS INTO PATHOGENESIS, DIAGNOSIS,...

Area of Science:

• Hematology
• Genetics
• Biochemistry

Background:

• GNE-related thrombocytopenia (GNE-RT) is a rare genetic disorder caused by GNE gene variants, leading to severe thrombocytopenia and bleeding.
• The exact mechanisms, particularly the impact on platelet biogenesis, remain poorly understood, with no established diagnostic tools.
• Previous findings suggested reduced platelet lifespan, but the effect on platelet production was unclear.

Purpose of the Study:

• To investigate the clinical features of GNE-RT.
• To explore the impact of GNE variants on megakaryopoiesis and platelet biogenesis.
• To evaluate diagnostic methods and treatment responses in GNE-RT patients.

Main Methods:

• Investigated 4 novel GNE-RT patients from 3 families.
• Utilized flow cytometry to assess platelet sialylation.
• Cultured patient-derived megakaryocytes and employed a 3D bone marrow model to study megakaryopoiesis and platelet production.

Main Results:

• Characterized 3 novel GNE variants, confirming pathogenicity of 2 VUS.
• Flow cytometry showed altered lectin binding (increased RCA-1/ECL, decreased MAL-II) in patient platelets.
• Despite sialylation defects, megakaryocytes exhibited normal differentiation, maturation, and proplatelet formation, producing normal platelets ex vivo.

Conclusions:

• Profound megakaryocyte sialylation defects in GNE-RT do not impair platelet biogenesis.
• Platelet flow cytometry using RCA-1 and MAL-II lectins is a reliable diagnostic assay for GNE-RT.
• Eltrombopag treatment in two patients resulted in a durable clinical response; literature suggests 55% of GNE-RT patients respond to thrombopoietin-mimetics.