Thrombocytopenia via the PTPRJ Gene

Inherited thrombocytopenias (IT) comprise a heterogeneous group of disorders characterized by platelet counts below the lower limit of normal: 150,000/µL (150 x 10⁹/L) in adults. Bleeding manifestations of thrombocytopenia range from mild to severe and may include excessive bruising (purpura), petechiae, prolonged bleeding from cuts or from surgical procedures, spontaneous nose bleeds, and in women, heavy menstrual flows. About half of ITs are syndromic disorders characterized by other physical and neurological anomalies, or immunodeficiencies (Balduini et al. 2013. PubMed ID: 23397552). Over 30 genes are known to be associated with ITs. Pathogenic variants in known genes are found in only about 50% of cases (Kunishima and Saito. 2006. PubMed ID: 16169642; Noris and Pecci. 2017. PubMed ID: 29222283). Noris and Pecci divide ITs into three groups: forms characterized by only platelet deficiencies, syndromic ITs with additional congenital defects, and ITs associated with increased risk of developing additional disease such as myelodysplastic syndrome (MDS) and acute leukemia (AL). For additional information regarding inherited hematologic malignancies, see Churpek et al. 2013. PubMed ID: 22691122; Furutani and Shimamura. 2017. PubMed ID: 28297620.

It is important to distinguish ITs from immune/idiopathic thrombocytopenias (ITP) in order to inform clinical management and identify potential at risk family members. The severity of ITs varies and disease may manifest within a few weeks of birth, or in patients with milder forms of IT symptoms may not appear until late adulthood. Given the genotypic and phenotypic heterogeneity found in IT patients, simultaneous genetic testing for a large subset of IT-related genes may provide the most efficient approach for establishing an accurate and timely diagnosis.

The list of genes associated with inherited thrombocytopenias continues to grow. Pathogenic variants in PTPRJ are associated with autosomal recessive inherited thrombocytopenia. Two siblings with congenital microthrombocytopenia were recently reported to have compound heterozygous loss of function variants in PTPRJ; each parent carried one of the variants (Marconi et al. 2019. PubMed ID: 30591527). The disease presented as nonsyndromic thrombocytopenia with mild to moderate bleeding tendencies, small platelets, and impaired megakaryocyte maturation and platelet formation. The patients showed a severe depletion of PTPRJ protein in blood cells and PTPRJ protein levels in the carrier parents were decreased by ~ 50%. To date, these are the only patients reported to have PTPRJ-related thrombocytopenia.

PTPRJ (also known as CD148) is a receptor-type protein tyrosine phosphatase expressed in megakaryocytes. PTPRJ is a master regulator of Src family kinases which are essential for platelet activation and clotting (Senis. 2013. PubMed ID: 24015866). Consistent with the human phenotype, knockdown studies of the ptprja protein in zebrafish (homolog of human PTPRJ) showed a decrease in proplatelet formation (Marconi et al. 2019. PubMed ID: 30591527). PTPRJ has been cited as a conditional gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

Roughly half of inherited thrombocytopenias are not yet characterized (Balduini et al. 2013. 23397552). Pathogenic variants in PTPRJ are a rare cause of inherited thrombocytopenias as only two siblings have been identified to date with PTPRJ-related inherited thrombocytopenia (Marconi et al. 2019. PubMed ID: 30591527).

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

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