Insights in Megakaryopoiesis and Platelet Biogenesis from Studies of Inherited Thrombocytopenias

Abstract

Inherited thrombocytopenias (ITs) are clinically and genetically heterogeneous disorders characterized by defects in megakaryopoiesis and platelet biogenesis. Patients with ITs have a variable degree or even no bleeding symptoms because of low platelet count that can be associated with platelet dysfunction. ITs have been described as an isolated blood disorder but can also be part of a multisystem disorder. Mutations in more than 30 genes have already been shown to be implicated in ITs and will be recapitulated in this review. Because of that complexity, detailed clinical and laboratory investigations are needed for diagnosis of ITs. However, confirmed diagnosis can usually only be made by genetic analysis. In this review paper, a focus is made on the major contributions of next-generation sequencing approaches to the genetic landscape of ITs. Numerous novel, often unexpected, genes have been identified; still more are expected, as about 50 % of the IT cases received not yet a genetic diagnosis. In addition, the phenotypic spectrum associated with a single gene also constantly gains in complexity as illustrated with some examples. All these factors make genotype-phenotype correlations particularly difficult. Finally, we highlight some functional genetic approaches that increasingly appear important to understand the role of novel genes in defective megakaryopoiesis and platelet biogenesis.