ADP Receptor Deficiency via the P2RY12 Gene

Adenosine diphosphate (ADP) receptor deficiency is a rare bleeding disorder only described in about 20 patients to date. Symptoms include epistaxis, easy bruising, mucosal bleeding, menorrhagia, and bleeding complications following trauma or surgery. Patients can be treated with platelet transfusions to mitigate bleeding episodes. Similar clinical features can be observed with patients on Clopidogrel, an inhibitor of the P2RY12 receptor, used as a blood thinner to prevent stroke and other cardiac problems (Cattaneo 2011; Hollopeter et al. 2001). Genetic testing can be helpful in differential diagnosis of ADP receptor deficiency from other platelet function disorders including Bernard-Soulier Syndrome, Glanzmann’s Thrombasthenia, and Hermansky-Pudlak syndrome (Watson et al. 2013).

ADP receptor deficiency is inherited in an autosomal recessive manner through pathogenic variants in the P2RY12 gene. Heterozygous patients have been reported to have a milder bleeding phenotype. Missense variants affecting protein stability and/or ADP binding have been reported throughout the coding region and represent about 2/3 of the causative variants (Daly et al. 2009; Cattaneo et al. 2003; Remijn et al. 2007; Lecci et al. 2015). Frameshift variants are found in about 1/3 of ADP receptor deficiency patients (Cattaneo 2011). The P2RY12 gene encodes a platelet ADP receptor which plays critical roles in regulating hemostasis and thrombosis. At sites of vessel injury, ADP is released and binds to the ADP receptors to activate platelet aggregation (Jin and Kunapuli 1998).

Clinical sensitivity cannot be estimated because only a small number of cases have been reported. Analytical sensitivity should be high because all pathogenic variants in the P2RY12 gene reported to date are detectable by sequencing.

This test provides full coverage of all coding exons of the P2RY12 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).