Thrombocytopenia Panel

Thrombocytopenia is a blood disorder 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 with additional defects including 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.

This panel test is designed to detect variants in several genes associated with either autosomal dominant, autosomal recessive, or X-linked forms of inherited thrombocytopenias. The genes included in this panel have been associated with both syndromic and non-syndromic forms of inherited thrombocytopenia and represent some of the more common forms of inherited thrombocytopenia reported in the literature. Thrombocytopenias are typically divided into three distinct groups based upon platelet size: large / macrothrombocytopenias, small / microthrombocytopenias, and thrombocytopenias with normal sized platelets.

Macrothrombocytopenias

MYH9--May-Hegglin Anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome. Inheritance is autosomal dominant. Clinical features may include high tone deafness, cataracts, leukocyte inclusions, and kidney disease leading in some cases to renal failure. Variants affecting the head domain of the Myosin-IIA protein are associated with a higher risk of nephropathy and deafness than variants affecting the tail domain (Pecci et al. 2014).

GP1BA, GP1BB, GP9--Bernard Soulier Syndrome and Platelet Type von Willebrand Disease (PT-VWD, GP1BA), and Giant Platelet Syndrome. Inheritance is autosomal recessive. Variants in GP1BA associated with PT-VWD are inherited in an autosomal dominant manner.

GATA1--X-linked thrombocytopenia. Inheritance is X-linked recessive. Clinical features include erythrocytic anemia, globin gene transcription defects, and porphyria.

Microthrombocytopenias WAS--Wiskott-Aldrich syndrome, X-linked thrombocytopenia. Inheritance is X-linked recessive. Clinical features may include eczema, recurrent bacterial and viral infections, severe hemorrhaging, autoimmune disease such as hemolytic anemia or immune thrombocytopenic purpura, lymphomas, and X-linked Congenital Neutropenia.

Thrombocytopenias with Normal Platelet Size

CYCS--Cytochrome-C gene related thrombocytopenia. Inheritance is autosomal dominant.

ANKRD26, MASTL--Thrombocytopenia 2 (THC2) is characterized by moderately low platelet counts (family averages = 40-60/nl) (Savoia et al. 1999; Drachman et al. 2000). Platelets are of normal size. Patients often bruise easily and have moderate bleeding problems. Thrombopoietin levels are mildly elevated. Variants in ANKRD26 are associated with predisposition to Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML); up to a 30 fold increase in the frequency of MDS and AML has been reported in patients with ANKRD26 gene variants (Noris et al. 2011; Noris et al. 2013; Marquez et al. 2014).

RUNX1--Familial Thrombocytopenia with Predisposition to Acute Myeloid Leukemia (AML). Inheritance is autosomal dominant. Over 40% of patients with germline variants in the RUNX1 gene develop MDS / AML at a mean age of ~ 33 years (Reviewed in Churpek et al. 2013).

MPL--Congenital Amegakaryocytic Thrombocytopenia (CAMT). Inheritance is autosomal recessive and variants in MPL have been identified in ~ 60% of patients. Clinical features include absent or reduced megakaryocytes and development of aplastic anemia and pancytopenia. AML has been reported in some patients (Ballmaier and Gerheshausen 2009).

ADAMTS13--Thrombotic Thrombocytopenic Purpura (TTP), often described as Upshaw-Schulman syndrome (USS), is a rare blood condition characterized by frequent relapses of fever, platelet thrombi in microvasculature, hemolytic anemia, consumptive thrombocytopenia, neurologic symptoms, renal disease, and possible organ failure (Levy et al. 2001). Inheritance is autosomal recessive.

See individual gene test descriptions for information on molecular biology of gene products.

This test is designed to identify variants in some of the more common genes associated with thrombocytopenias. While the overall clinical sensitivity of this panel is difficult to determine, in a recent study of 272 patients with macrothrombocytopenia, ~48% of patients harbored pathogenic variants in either the MYH9 gene (~ 38%), the Bernard Soulier genes (~ 10%), or the GATA1 gene (< 1%) (Kunishima, S. Thrombocytopenia, ISTH Webinar 2015: WEB150325). In general, ~ 50% of inherited thrombocytopenias are the result of disorders that are not yet characterized (Balduini et al. 2013).

The majority of variants reported in the thrombocytopenia genes in this panel are missense and nonsense variants. Large deletions account for ~24% of the reported RUNX1 gene variants, but in general, large, multi-exon and whole gene deletions are rare among the thrombocytopenia panel genes. In addition to the RUNX1 gene, large deletions have also been reported in the GP1BB, MYH9, and WAS genes (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).