Detection of a novel, germline variant in the GP1BA gene causing monoallelic Bernard-Soulier syndrome in a large pedigree with inherited macrothrombocytopenia

Introduction Classical Bernard-Soulier syndrome (BSS) is an autosomal recessive platelet disorder caused by biallelic mutations in GP1BA , GP1BB or GP9 gene , which encode the subunits of the glycoprotein (GP) Ib-IX-V complex, the platelet receptor for von Willebrand factor. Affected patients display clinically relevant bleeding symptoms and present with moderate-to-severe macrothrombocytopenia, reduced or even abolished expression of GP Ib-IX-V and a significant defect of platelet adhesion. Monoallelic mutations hitting GP1BA or GP1BB can lead to a more frequent form of BSS presenting with mild inherited macrothrombocytopenia, partially diminished expression of GP Ib-IX-V and mild if any platelet disfunction. Although the bleeding phenotype is generally mild, accurate diagnosis of monoallelic BSS is advisable to avoid undue and possible harmful treatments, often resulting from a misdiagnosis as immune thrombocytopenia (ITP). We report on a subject belonging to a large pedigree with monoallelic BSS due to a hitherto unreported variant in the GP1BA . Method Platelet phenotype was assessed with whole blood cell count, flow cytometry, light- and immunofluorescence microscopy. Molecular analysis was performed through next-generation sequencing (NGS), followed by family genotyping using Sanger sequencing. Results The index subject was a 15-year-old male of Caucasian origin referred for the diagnostic evaluation of an incidentally discovered thrombocytopenia. He presented with mild thrombocytopenia (mean platelet count: 139 10 9 /L) and mild bleeding tendency (ISTH BAT score: 1). Light microscopy revealed platelet macrocytosis with occasional giant platelets. Immunofluorescence microscopy showed partially reduced expression of GP Ib alpha and -beta, which was confirmed by flow cytometry. The combination of these findings and a family history of thrombocytopenia with typical autosomal-dominant inheritance pattern, raised the suspicion of monoallelic BSS. Molecular analysis detected a heterozygous missense variant located in the exon 2 of the GP1BA gene (NM_000173.7): c.455T>C, p.(Leu152Pro) not reported in gnomAD or other major public population databases. The variant segregated with the phenotype across three generations. This alteration, causing a replacement of a leucine with a proline in a leucine-rich repeat domain, is predicted to destabilize the conformation, and thereby the stability and function, of the GP Ib-IX-V complex. On this basis, we classified the variant as a likely pathogenic . Conclusion The reported novel variant in GP1BA enlarges the spectrum of mutations causing monoallelic BSS, which represents one of the less rare causes of inherited macrothrombocytopenia in Europe. The present case underscores the critical importance of detailed family history and platelet morphology as simple yet powerful tools for the early recognition of this condition [ 1 ] [ 2 ]. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany