Rare variants in GP1BB are responsible for autosomal dominant macrothrombocytopenia

摘要

The von Willebrand receptor complex, which is composed of the glycoproteins Ibα and Ibβ, V and IX, plays an essential role in the earliest steps in hemostasis. Over the last four decades, it has become apparent that loss of function of any one of three of the genes encoding these glycoproteins namely, GP1BA, GP1BB and GP9, leads to autosomal recessive macrothrombocytopenia complicated by bleeding. A small number of variants in GP1BA have been reported to cause a milder and dominant form of macrothrombocytopenia but only two tentative reports exists of such a variant in GP1BB. By analyzing data from a collection of over 1,000 genome-sequenced patients with a rare bleeding and/or platelet disorder, we have identified a significant association between rare monoallelic variants in GP1BB and macrothrombocytopenia. In order to strengthen our findings, we sought further cases in two additional collections in the UK and Japan. Across 18 families exhibiting phenotypes consistent with autosomal dominant inheritance of macrothrombocytopenia, we report on 27 affected cases carrying one of 9 rare variants in GP1BB.