Characterization of Novel Variants in P2YRY12, GP6 and TBXAS1 in Patients with Lifelong History of Bleeding

Inherited platelet function disorders (IPFDs) are rare diseases caused by defects in platelet surface receptors, enzymes, granules, or signaling proteins. In humans, GPVI and P2Y12 deficiency cause autosomal recessive bleeding disorders, while TBXAS1 deficiency is related to Ghosal hematodiaphyseal dysplasa, a rare autosomal recessive disorder characterized by increased long bone density and platelet dysfunction without bleeding. To date, at least 20 patients have been identified with molecular defects in <i>P2RY12</i>, 12 cases with molecular defects in <i>GP6</i>, and 34 cases with molecular defects in <i>TBXAS1</i>. Here, we report a novel nonsense and missense variants in <i>P2RY12</i>, a novel nonsense variant in <i>GP6</i>, and a novel missense variant in <i>TBXAS1</i>. These variants selectively affect the platelet reactivity to ADP and collagen/CRP, predisposing to bleeding. <i>P2RY12</i> c.835 G>A [p.Val279Met] variant did not affect receptor expression whereas <i>P2RY12</i> c.44delG [p.Ser15Ilefs*33] lead to decreased levels of the receptor in one of the patients. This was confirmed both by RT-qPCR and immunoblotting analysis. Decreased expression of both GPVI and FcRγ-chain was detected in patients carrying GPVI nonsense variant in heterozygosis. The deleterious effect of these variants was also confirmed in a transfected cell line model. <i>TBXAS1</i> variant triggered decreased TxA₂ production using a cell line model. These variants expand the genetic landscape of P2RY12, GPVI and TBXAS1 inherited deficiency.