Molecular Genetics of Inherited Thrombocytopenias

Abstract

Inherited thrombocytopenias (ITs) are rare, clinically and genetically heterogeneous diseases caused by mutations in more than 30 genes. Considering that they account for approximately 50% of the cases, many other genetic unknown factors are likely to be involved. The IT genes encode for proteins playing numerous functions, participating in the different steps of megakaryopoiesis, such as differentiation and production of mature megakaryocytes, and platelet release in the blood stream. Mutations impairing any of these processes lead to reduction of platelet count. While in some ITs, thrombocytopenia is the only feature, in others, it is associated with other haematological defects and/or clinical manifestations. Not always the pathogenic mechanisms are known, mainly because our knowledge on protein function is limited. However, the number of the IT genes is increasing rapidly, and combining genetic and functional studies will allow us to unravel the complex network of interactions controlling platelet biogenesis.

Key Concepts

  • Inherited thrombocytopenias (ITs) are characterised by clinical and genetic heterogeneity.
  • Reduction in platelet count can be due to defects in any phase of megakaryocyte and platelet production.
  • Mutations in more than 30 different genes cause ITs.
  • The IT gene products play many different, sometimes unknown roles in the processes of platelet production.
  • Mutations in the known genes explain the disease in only 50% of families with IT.
  • Application of next‐generation sequencing strategies in large case series of affected individuals will allow us to characterise novel ITs and understand the molecular basis of these diseases more extensively.

Keywords: inherited thrombocytopenia; bleeding; megakaryocytopoiesis; platelet biogenesis; disease‐causing gene

Figure 1. Clinical features in ITs. In addition to isolated thrombocytopenia, the low platelet number can be associated with platelet dysfunction, additional haematological manifestations or other clinical symptoms, which might be congenital or develop during life. ACTN1‐RT, ACTN1‐related thrombocytopenia; ANKRD26‐RT, ANKRD26‐related thrombocytopenia; ARPC1B‐RD, ARPC1B‐related disease; BSS, Bernard–Soulier syndrome; CAMT, congenital amegakaryocytic thrombocytopenia; DIAPH1‐RD, DIAPH1‐related disease; ETV6‐RT, ETV6‐related thrombocytopenia; FYB‐RT, FYB‐related thrombocytopenia; FLI1‐RT, FLI1‐related thrombocytopenia; FLNA‐RT, FLNA‐related thrombocytopenia; GATA1‐RD, GATA1‐related disease; GFI1B‐RT, GFI1B‐related thrombocytopenia; GPS, grey platelet syndrome; FPD/AML, familial platelet disorder with associated myeloid malignancy; ITGA2B‐ITGB3‐RT, ITGA2B‐ITGB3‐related thrombocytopenia; JBS, Jacobsen syndrome; MYH9‐RD, MYH9‐related disease; PRKACG‐RT, PRKACG‐related‐thrombocytopenia; PVNH, periventricular nodular heterotopia; RUSAT, radioulnar synostosis with amegakaryocytic thrombocytopenia; THPO‐RD: THPO‐related disease; TAR, thrombocytopenia‐absent radius syndrome; TUBB1‐RT, TUBB1‐related thrombocytopenia; XLT, X‐linked thrombocytopenia; WAS, Wiskott–Aldrich syndrome.
Figure 2. Schematic representation of megakaryopoiesis and platelet production, showing different steps of the process, such as differentiation and maturation of megakaryocytes (MKs), proplatelet production and platelet release into blood stream. Each phase is controlled by products of genes whose mutations are responsible for ITs, which might be characterised by significant reduction of MKs, generation of immature MKs or defective processes in proplatelet extension.
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Pecci A (2015) Diagnosis and treatment of inherited thrombocytopenia. Clinical Genetics 89 (2): 141–153.

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Savoia, Anna(Aug 2017) Molecular Genetics of Inherited Thrombocytopenias. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027326]