Thrombocytopenia and Bleeding Disorder, Platelet Type 19 via the PRKACG Gene

Inherited thrombocytopenias (IT) comprise a heterogeneous group of disorders characterized by platelet counts below the lower limit of normal, below 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.

Pathogenic variants in PRKACG are associated with a rare form of inherited thrombocytopenia defined as bleeding disorder, platelet-type, 19 (BDPLT19) that has been reported in only one family to date (Manchev et al. 2014. PubMed ID:25061177). PRKACG-related thrombocytopenia is characterized by severe thrombocytopenia (5-8/µL), large platelets, moderate bleeding, epistaxis, and cutaneous hematomas (Manchev et al. 2014. PubMed ID:25061177).

Inheritance is autosomal recessive and to date, only one pathogenic variant in PRKACG has been reported to be causative for thrombocytopenia. A homozygous missense variant, c.222C>G (p.Ile74Met), was reported in one family with a history of early childhood onset, severe macrothrombocytopenia, and bleeding diatheses (Manchev et al. 2014. PubMed ID: 25061177).

The PRKACG gene encodes the γ-catalytic subunit of the cyclic adenosine monophosphate-dependent protein kinase. Data suggest that the PRKACG protein plays a role in proplatelet formation and that pathogenic variants have a negative effect on the platelet cytoskeletal protein filamin A (Manchev et al. 2014. PubMed ID: 25061177).

Over 30 genes are known to be associated with inherited thrombocytopenias (IT). 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). PRKACG-related IT is a rare form of IT which has been reported in only one family to date.

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV-calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

This test provides full coverage of all coding exons of the PRKACG gene plus coverage of 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).