Progress in understanding the diagnosis and molecular genetics of macrothrombocytopenias

The inherited macrothrombocytopenias constitute a subgroup of congenital platelet disorders that is the best characterized from the genetic point of view. This clinically heterogeneous subgroup is characterized by a variable degree of bleeding but without predisposition to haematological malignancies, as seen in the two other subgroups. The classification of inherited thrombocytopenia is traditionally based on the description of different clinical and biological features, in particular the measurement of the mean platelet volume. In certain disorders, biochemical platelet components are abnormal, and their analyses are useful in diagnosis. However, these approaches present several limitations, and many cases remain undiagnosed, especially for patients without a clear family history. An analysis of genetic abnormalities was subsequently used for classification, demonstrating that some different clinical entities were, in fact, identical. The genomic approach that was used initially to accurately link some phenotypic diagnoses with the causal genetic alteration was positional cloning and DNA sequencing. More recently, next generation sequencing in the form of whole-genome or -exome sequencing and RNA sequencing has been developed. This review will focus on the progress in understanding the different macrothrombocytopenias that have been identified.