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 P2RY12, 12 cases with molecular defects in GP6, and 34 cases with molecular defects in TBXAS1. Here, we report a novel nonsense and missense variants in P2RY12, a novel nonsense variant in GP6, and a novel missense variant in TBXAS1. These variants selectively affect the platelet reactivity to ADP and collagen/CRP, predisposing to bleeding. P2RY12 c.835 G>A [p.Val279Met] variant did not affect receptor expression whereas P2RY12 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. TBXAS1 variant triggered decreased TxA2 production using a cell line model. These variants expand the genetic landscape of P2RY12, GPVI and TBXAS1 inherited deficiency.