Abstract
Inherited thrombocytopenia (IT) is comprised of a group of hereditary disorders characterized by a reduced platelet count as the main feature, and often with abnormal platelet function, which can subsequently lead to impaired haemostasis. Inherited thrombocytopenia results from genetic mutations in genes implicated in megakaryocyte differentiation and/or platelet formation and clearance. The identification of the underlying causative gene of IT is challenging given the high degree of heterogeneity, but important due to the presence of various clinical presentations and prognosis, where some defects can lead to hematological malignancies. Traditional platelet function tests, clinical manifestations, and hematological parameters allow for an initial diagnosis. However, employing Next-Generation Sequencing (NGS), such as Whole Genome and Whole Exome Sequencing (WES) can be an efficient method for discovering causal genetic variants in both known and novel genes not previously implicated in IT. To date, 40 genes and their mutations have been implicated to cause many different forms of inherited thrombocytopenia. Nevertheless, despite this advancement in the diagnosis of IT, the molecular mechanism underlying IT in some patients remains unexplained. In this review, we will discuss the genetics of thrombocytopenia summarizing the recent advancement in investigation and diagnosis of IT using phenotypic approaches, high-throughput sequencing, targeted gene panels, and bioinformatics tools.
Highlights
Platelets are small anucleate cells produced by megakaryocytes in the bone marrow (BM) where they circulate in the blood to protect the integrity of blood vessels
Inherited Thrombocytopenias (ITs) are a heterogeneous group of disorders characterized by low platelet counts, often manifesting as bleeding diathesis which subsequently result in impaired haemostasis [3]
These defects are variable in severity, ranging from severe bleeding, which can be recognized within a few weeks after birth, to mild bleeding that may remain undiagnosed until incidental recognition during
Summary
Platelets are small anucleate cells produced by megakaryocytes in the bone marrow (BM) where they circulate in the blood to protect the integrity of blood vessels. 40 genes have been reported to cause different forms of IT, which reflects the immense difficulty in identifying a single causative gene, when accompanied by other hematological disorders [Table 1; Figure 1; [27, 28, 54]] These genetic forms have various clinical manifestations, phenotypic presentations and sometimes associated with secondary qualitative defects in platelet function [7]. Diverse platelet phenotypes mean there are several approaches in which they can be characterized One such way is to classify genes based on their influence on megakaryocyte differentiation, platelet production, and removal [54], and will be discussed below. Despite these advancements, nearly 50% of patients with IT of unknown genetic etiology still remain undiagnosed [6, 10]
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