Paris-Trousseau Thrombocytopenia via the FLI1 Gene

Inherited thrombocytopenias comprise a heterogeneous group of rare disorders characterized by low platelet counts. In adults, low platelet numbers are typically considered below 150,000/microL. Bleeding manifestations of thrombocytopenia include excessive bruising (purpura), petechiae, prolonged bleeding from cuts or from surgical procedures, spontaneous nose bleeds, and in women, heavy menstrual flows. Thrombocytopenia and consequent bleeding diatheses range in severity from mild to severe. About half of the inherited thrombocytopenias are syndromic disorders characterized by physical and neurological anomalies, and immunodeficiencies (Balduini et al. 2013). Some inherited thrombocytopenias are associated with an increased risk of developing myelodysplastic syndrome (MDS) and acute leukemia (AL) (Churpek et al. 2013). It is important to distinguish inherited thrombocytopenias from immune/idiopathic thrombocytopenias (ITP) in order to inform clinical management and identify potential at risk family members.

Paris-Trousseau syndrome and Jacobsen syndrome are overlapping disorders characterized by thrombocytopenia, facial and cardiac dysmorphism, growth restrictions and intellectual disability (Krishnamurti et al. 2001; Favier et al. 2003). These disorders are associated with deletions encompassing chromosome 11q. Platelets in patients with Paris-Trousseau syndrome and Jacobsen syndrome are large and contain giant alpha granules. The FLI1 gene is a transcription factor involved in megakaryocyte differentiation that resides on chromosome 11q and is located in the deleted region found in Paris-Trousseau syndrome and Jacobsen syndrome patients. Hemizygous loss of FLI1 and monoallelic expression are thought to contribute to the platelet phenotype found in Paris-Trousseau syndrome and Jacobsen syndrome patients (Raslova et al. 2004). Missense variants in FLI1 have also been reported in families with bleeding phenotypes and platelet dense granule secretion defects (Stockley et al. 2013).

Paris-Trousseau Thrombocytopenia is caused by pathogenic variants in the FLI1 gene; inheritance is autosomal dominant, though a case of apparent recessive inheritance in a consanguineous family was reported (Stevenson et al. 2015). FLI1 encodes a transcription factor found primarily in hematopoietic cells and that regulates gene expression during megakaryopoiesis (Bastian et al. 1999). To date, only a few pathogenic missense variants and one small deletion resulting in premature protein termination have been reported. All these variants have been located in the conserved ETS DNA-binding domain important for transcription factor function (Stevenson et al. 2015).

In one study, FLI1 pathogenic variants were found in 3 of 13 unrelated patients with thrombocytopenia and dense granule secretion defects suggesting that FLI1-related thrombocytopenias may be one of the more abundant forms of inherited thrombocytopenias (Stockley et al. 2013). Stockley et al. (2013) reported that relatives of affected individuals were also affected, suggesting that penetrance of dominant FLI1 variants is high.

This test provides full coverage of all coding exons of the FLI1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).