[Molecular genetics of paroxysmal nocturnal hemoglobinuria]

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic disorder caused by mutations affecting the biosynthesis of glycosylphosphatidylinositol (GPI) anchors. Recent advances in genetic analyses have shown that, in addition to PIGA mutations, rare mutations in PIGT, PIGB, and PIGV can also underlie PNH. Moreover, PNH may have an oligoclonal structure, and small PIGA-mutated clones can be detected even in healthy individuals. The expansion of PNH clones is thought to be driven not only by immune-mediated selective pressure but also, in some cases, by HMGA2 mutations and myeloid driver lesions, suggesting that PNH develops through multifactorial mechanisms that vary among patients. In addition, the genetic factors involved in progression to secondary myeloid neoplasms and response to complement inhibitors are becoming better understood. This article reviews the genetic findings relevant to PNH and discusses their clinical significance.