Thrombocytopenia via the GFI1B 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 primarily 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. PubMed ID: 23397552). Some inherited thrombocytopenias are associated with an increased risk of developing myelodysplastic syndrome (MDS) and acute leukemia (AL) (Churpek et al. 2013. PubMed ID: 22691122). 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.

GFI1B encodes a transcription factor essential for erythropoiesis and megakaryopoiesis. Pathogenic variants in GFI1B are associated with abnormal megakaryocytes and platelets and result in macrothrombocytopenia with a variable bleeding phenotype and the presence of red cell anisopoikilocytosis (Stevenson et al. 2013. PubMed ID: 23927492; Monteferrario et al. 2014. PubMed ID: 24325358). Inheritance is autosomal dominant. Abnormal GFI1B protein may act in a dominant negative manner resulting in thrombocytopenia with alpha-granule deficiency and the characteristic gray appearance found in Gray Platelet syndrome (Stevenson et al. 2013. PubMed ID: 23927492; Monteferrario et al. 2014. PubMed ID: 24325358; Kitamura et al. 2016. PubMed ID: 27122003). Missense, nonsense, and splice site variants have been reported in patients with GFI1B-related macrothrombocytopenia.

About two-thirds of patients with congenital macrothrombocytopenia are found to have variants in one of the following genes: MYH9, GP1BA, GP1BB, GP9, ITGA2B, ITGB3, or ACTN1 (Kunishima et al. 2013. PubMed ID: 23434115). Variants in the GFI1B gene have so far been found in only a few patients and appear to be a much less frequent cause of thrombocytopenia.

About two-thirds of patients with congenital macrothrombocytopenia are found to have variants in one of the following genes: MYH9, GP1BA, GP1BB, GP9, ITGA2B, ITGB3, or ACTN1 (Kunishima et al. 2013. PubMed ID: 23434115). Pathogenic variants in the GFI1B gene have so far been found in only a few patients and appear to be a much less frequent cause of thrombocytopenia.

This test provides full coverage of all coding exons of the GFI1B 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).