Gene mutations associated with thrombosis detected by whole‐exome sequencing in paroxysmal nocturnal hemoglobinuria

BACKGROUND: Thrombosis is a most common and lethal complication of paroxysmal nocturnal hemoglobinuria (PNH), which is a complex progression and its mechanism remains unclear. We tried to explore the possible genetic background of thrombosis in PNH patients and provide potential gene mutations associated with thrombosis in PNH patients. METHODS: The CD59- cells of 7 PNH and 6 PNH- aplastic anemia (AA) patients were sorted by flow cytometry and sequenced by whole-exome sequencing (WES). The sequencing results and target mutation genes were analyzed and screened, respectively, and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway enrichment analysis was carried out. Finally, the expression of target genes was detected in 22 PNH (including seven cases with thrombus) and 20 normal controls, and the correlation between the expression of mRNA and the clinical thrombus-related indexes was analyzed. RESULTS: The mutation genes screened from 4 PNH with thrombus were BMPR2, F8, ITGA2B, THBD, and THBS1. The pathways enriched by these genes included Notch, Wnt, and arachidonic acid metabolism signaling pathways, which may be related to the pathogenesis of thrombosis in PNH. The BMPR2, THBD, and THBS1 gene expression was significantly different between PNH with and without thrombus group, and the THBS1 gene expression was positively correlated with D-Dimer and su-PAR levels. CONCLUSIONS: Genetic defects have a non-negligible effect on the incidence of thrombosis, and therefore, gene mutations maybe a genetic risk factor in PNH, which increase the incidence of thrombosis.