Molecular Genetics of Inherited Thrombocytopenias


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.


Albers CA, Paul DS, Schulze H, et al. (2012) Compound inheritance of a low‐frequency regulatory SNP and a rare null mutation in exon‐junction complex subunit RBM8A causes TAR syndrome. Nature Genetics 44 (4): 435–439, S1‐2.

Albert MH, Bittner TC, Nonoyama S, et al. (2010) X‐linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long‐term outcome, and treatment options. Blood 115 (16): 3231–3238.

Balduini CL, Melazzini F and Pecci A (2017) Inherited thrombocytopenias – recent advances in clinical and molecular aspects. Platelets 28 (1): 3–13.

Ballmaier M and Germeshausen M (2011) Congenital amegakaryocytic thrombocytopenia: clinical presentation, diagnosis, and treatment. Seminars in Thrombosis Hemostasis 37 (6): 673–681.

Berrou E, Adam F, Lebret M, et al. (2013) Heterogeneity of platelet functional alterations in patients with filamin A mutations. Arteriosclerosis Thrombosis and Vascular Biology 33 (1): e11–e18.

Bluteau D, Balduini A, Balayn N, et al. (2014) Thrombocytopenia‐associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation. Journal of Clinical Investigation 124 (2): 580–591.

Bottega R, Pecci A, De Candia E, et al. (2013) Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α‐granule deficiency. Haematologica 98 (6): 868–874.

Bottega R, Marconi C, Faleschini M, et al. (2015) ACTN1‐related thrombocytopenia: identification of novel families for phenotypic characterization. Blood 125 (5): 869–872.

Campbell AE, Wilkinson‐White L, Mackay JP, et al. (2013) Analysis of disease‐causing GATA1 mutations in murine gene complementation systems. Blood 121 (26): 5218–5227.

Chen Z, Naveiras O, Balduini A, et al. (2007) The May‐Hegglin anomaly gene MYH9 is a negative regulator of platelet biogenesis modulated by the Rho‐ROCK pathway. Blood 110 (1): 171–179.

Curcio C, Pannellini T, Lanzardo S, et al. (2007) WIP null mice display a progressive immunological disorder that resembles Wiskott–Aldrich syndrome. Journal of Pathology 211 (1): 67–75.

Dasouki MJ, Rafi SK, Olm‐Shipman AJ, et al. (2013) Exome sequencing reveals a thrombopoietin ligand mutation in a Micronesian family with autosomal recessive aplastic anemia. Blood 122 (20): 3440–3449.

De Rocco D, Cerqua C, Goffrini P, et al. (2014) Mutations of cytochrome c identified in patients with thrombocytopenia THC4 affect both apoptosis and cellular bioenergetics. Biochimica et Biophysica Acta 1842 (2): 269–274.

Fletcher SJ, Johnson B, Lowe GC, et al. (2015) SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects. Journal of Clinical Investigation 125 (9): 3600–3605.

Gunay‐Aygun M, Falik‐Zaccai TC, Vilboux T, et al. (2011) NBEAL2 is mutated in gray platelet syndrome and is required for biogenesis of platelet α‐granules. Nature Genetics 43 (8): 732–734.

Hamamy H, Makrythanasis P, Al‐Allawi N, et al. (2014) Recessive thrombocytopenia likely due to a homozygous pathogenic variant in the FYB gene: case report. BMC Medical Genetics 15: 135.

Kahr WH, Lo RW, Li L, et al. (2013) Abnormal megakaryocyte development and platelet function in Nbeal2(‐/‐) mice. Blood 122 (19): 3349–3358.

Kahr WH, Pluthero FG, Elkadri A, et al. (2017) Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease. Nature Communications 8: 14816.

Kashiwagi H, Kunishima S, Kiyomizu K, et al. (2013) Demonstration of novel gain‐of‐function mutations of αIIbβ3: association with macrothrombocytopenia and glanzmann thrombasthenia‐like phenotype. Molecular Genetics and Genomic Medicine 1 (2): 77–86.

Kunishima S, Okuno Y, Yoshida K, et al. (2013) ACTN1 mutations cause congenital macrothrombocytopenia. American Journal of Human Genetics 92 (3): 431–438.

Kunishima S, Nishimura S, Suzuki H, et al. (2014) TUBB1 mutation disrupting microtubule assembly impairs proplatelet formation and results in congenital macrothrombocytopenia. European Journal of Haematology 92 (4): 276–282.

Lanzi G, Moratto D, Vairo D, et al. (2012) A novel primary human immunodeficiency due to deficiency in the WASP‐interacting protein WIP. Journal of Experimental Medicine 209 (1): 29–34.

Levin C, Koren A, Pretorius E, et al. (2015) Deleterious mutation in the FYB gene is associated with congenital autosomal recessive small‐platelet thrombocytopenia. Journal of Thrombosis and Haemostasis 13 (7): 1285–1292.

Mahlaoui N, Pellier I, Mignot C, et al. (2013) Characteristics and outcome of early‐onset, severe forms of Wiskott–Aldrich syndrome. Blood 121 (9): 1510–1516.

Manchev VT, Hilpert M, Berrou E, et al. (2014) A new form of macrothrombocytopenia induced by a germ‐line mutation in the PRKACG gene. Blood 124 (16): 2554–2563.

Marconi C, Di Buduo CA, Barozzi S, et al. (2016) SLFN14‐related thrombocytopenia: identification within a large series of patients with inherited thrombocytopenia. Thrombosis and Haemostasis 115 (5): 1076–1079.

Melazzini F, Palombo F, Balduini A, et al. (2016) Clinical and pathogenic features of ETV6‐related thrombocytopenia with predisposition to acute lymphoblastic leukemia. Haematologica 101 (11): 1333–1342.

Millikan PD, Balamohan SM, Raskind WH, et al. (2011) Inherited thrombocytopenia due to GATA‐1 mutations. Seminars in Thrombosis Hemostasis 37 (6): 682–689.

Monteferrario D, Bolar NA, Marneth AE, et al. (2014) A dominant‐negative GFI1B mutation in the gray platelet syndrome. New England Journal of Medicine 370 (3): 245–253.

Morison IM, Cramer Bordé EM, Cheesman EJ, et al. (2008) A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia. Nature Genetics 40 (4): 387–389.

Niihori T, Ouchi‐Uchiyama M, Sasahara Y, et al. (2015) Mutations in MECOM, encoding oncoprotein EVI1, cause radioulnar synostosis with amegakaryocytic thrombocytopenia. American Journal of Human Genetics 97 (6): 848–854.

Noetzli L, Lo RW, Lee‐Sherick AB, et al. (2015) Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nature Genetics 47 (5): 535–538.

Noris P, Perrotta S, Seri M, et al. (2011) Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families. Blood 117 (24): 6673–6680.

Noris P, Marconi C and Rocco D (2017) A new form of inherited thrombocytopenia due to monoallelic loss of function mutation in the thrombopoietin gene. British Journal of Haematology. DOI: 10.1111/bjh.14694.

Nurden P, Debili N, Coupry I, et al. (2011) Thrombocytopenia resulting from mutations in filamin A can be expressed as an isolated syndrome. Blood 118 (22): 5928–5937.

Pecci A, Biino G, Fierro T, et al. (2012) Alteration of liver enzymes is a feature of the Myh9‐related disease syndrome. Plos One 7 (4): e35986.

Pecci A, Klersy C, Gresele P, et al. (2014) MYH9‐related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype‐phenotype correlations. Human Mutation 35 (2): 236–247.

Raslova H, Komura E, Le Couédic JP, et al. (2004) FLI1 monoallelic expression combined with its hemizygous loss underlies Paris‐Trousseau/Jacobsen thrombopenia. Journal Clinical of Investigation 114 (1): 77–84.

Sabri S, Foudi A, Boukour S, et al. (2006) Deficiency in the Wiskott–Aldrich protein induces premature proplatelet formation and platelet production in the bone marrow compartment. Blood 108 (1): 134–140.

Savoia A, Kunishima S, De Rocco D, et al. (2014) Spectrum of the mutations in Bernard–Soulier syndrome. Human Mutation 35 (9): 1033–1045.

Song WJ, Sullivan MG, Legare RD, et al. (1999) Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nature Genetics 23 (2): 166–175.

Stevenson WS, Morel‐Kopp MC, Chen Q, et al. (2013) GFI1B mutation causes a bleeding disorder with abnormal platelet function. Journal of Thrombosis and Haemostasis 11 (11): 2039–2047.

Stevenson WS, Rabbolini DJ, Beutler L, et al. (2015) Paris‐Trousseau thrombocytopenia is phenocopied by the autosomal recessive inheritance of a DNA‐binding domain mutation in FLI1. Blood 126 (17): 2027–2030.

Stockley J, Morgan NV, Bem D, et al. (2013) Enrichment of FLI1 and RUNX1 mutations in families with excessive bleeding and platelet dense granule secretion defects. Blood 122 (25): 4090–4093.

Stritt S, Nurden P, Turro E, et al. (2016a) A gain‐of‐function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss. Blood 127 (23): 2903–2914.

Stritt S, Nurden P, Favier R, et al. (2016b) Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg(2+) homeostasis and cytoskeletal architecture. Nature Communications 7: 11097.

Thompson AA and Nguyen LT (2000) Amegakaryocytic thrombocytopenia and radio‐ulnar synostosis are associated with HOXA11 mutation. Nature Genetics 26 (4): 397–398.

Turro E, Greene D, Wijgaerts A, et al. (2016) A dominant gain‐of‐function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies. Science Translational Medicine 8 (328): 328ra330.

Further Reading

Balduini CL, Pecci A and Savoia A (2011) Recent advances in the understanding and management of MYH9‐related inherited thrombocytopenias. British Journal of Haematology 154 (2): 161–174.

Lopez JA, Andrews RK, Afshar‐Kharghan V, et al. (1988) Bernard–Soulier syndrome. Blood 91 (12): 4397–4418.

Machlus KR, Thon JN and Italiano JE (2014) Interpreting the developmental dance of the megakaryocyte: a review of the cellular and molecular processes mediating platelet formation. British Journal of Haematology 165 (2): 227–236.

Massaad MJ, Ramesh N and Geha RS (2013) Wiskott–Aldrich syndrome: a comprehensive review. Annals of the New York Academy of Sciences 1285: 26–43.

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. [doi: 10.1002/9780470015902.a0027326]