Genetics of inherited thrombocytopenias

Abstract

The inherited thrombocytopenia syndromes are a group of disorders characterized primarily by quantitative defects in platelet number, though with a variety demonstrating qualitative defects and/or extrahematopoietic findings. Through collaborative international efforts applying next-generation sequencing approaches, the list of genetic syndromes that cause thrombocytopenia has expanded significantly in recent years, now with over 40 genes implicated. In this review, we focus on what is known about the genetic etiology of inherited thrombocytopenia syndromes and how the field has worked to validate new genetic discoveries. We highlight the important role for the clinician in identifying a germline genetic diagnosis and strategies for identifying novel causes through research-based endeavors.

Graphical abstract

Figure 1.

Genes that cause inherited thrombocytopenias grouped by established and potential cellular mechanisms involved in megakaryocyte biology. These genes also correspond to the tier 1 and tier 2 gene lists curated by the International Society of Thrombosis and Hemostasis Genomics in Hemostasis Subcommittee.

Figure 2.

Complex Venn diagram showing the extrahematopoietic manifestations of select germline inherited thrombocytopenia syndromes. *The role of GP1BB in the thrombocytopenia associated with 22q11 del has been recently disputed (see Zwifelhofer et al⁴²).