A GP1BA Variant in a Czech Family with Monoallelic Bernard-Soulier Syndrome

Abstract

Bernard-Soulier syndrome (BSS) is a rare inherited disorder characterized by unusually large platelets, low platelet count, and prolonged bleeding time. BSS is usually inherited in an autosomal recessive (AR) mode of inheritance due to a deficiency of the GPIb-IX-V complex also known as the von Willebrand factor (VWF) receptor. We investigated a family with macrothrombocytopenia, a mild bleeding tendency, slightly lowered platelet aggregation tests, and suspected autosomal dominant (AD) inheritance. We have detected a heterozygous GP1BA likely pathogenic variant, causing monoallelic BSS. A germline GP1BA gene variant (NM_000173:c.98G > A:p.C33Y), segregating with the macrothrombocytopenia, was detected by whole-exome sequencing. In silico analysis of the protein structure of the novel GPIbα variant revealed a potential structural defect, which could impact proper protein folding and subsequent binding to VWF. Flow cytometry, immunoblot, and electron microscopy demonstrated further differences between p.C33Y GP1BA carriers and healthy controls. Here, we provide a detailed insight into its clinical presentation and phenotype. Moreover, the here described case first presents an mBSS patient with two previous ischemic strokes.

Biological, clinical features and modelling of heterozygous variants of glycoprotein Ib platelet subunit alpha (GP1BA) and glycoprotein Ib platelet subunit beta (GP1BB) genes responsible for constitutional thrombocytopenia

“…For this, it would be necessary to analyse larger series of patients and to carry out directed mutagenesis studies. It would also be interesting to compare the proteomics of these variants with that of normal individuals, as performed by immunoblot for GP1BA p.Cys33Tyr by Skalníková et al 13 Finally, the results of this study suggest that variants affecting the GP1BA and GP1BB genes are a fairly frequent cause of MTP. It is nonetheless probably underestimated, especially as patients display moderate thrombocytopenia with an often mild haemorrhagic phenotype.…”

“…For this, it would be necessary to analyse larger series of patients and to carry out directed mutagenesis studies. It would also be interesting to compare the proteomics of these variants with that of normal individuals, as performed by immunoblot for GP1BA p.Cys33Tyr by Skalníková et al 13 …”

“…The latter are called monoallelic BSS with an autosomal dominant transmission. 4 To date, 13 GP1BA variants [4][5][6][7][8][9][10][11][12][13][14][15][16] and 14 GP1BB variants, [15][16][17][18][19][20][21][22] considered to be responsible for monoallelic BSS, have been described in the literature (Table 1). [4][5][6][7][8][9][10][11][13][14][15][16][17][18][19][20][21]23 No variant responsible for monoallelic BSS has been identified to date in the GP9 gene.…”

“…Clinically, patients present with moderate mucocutaneous bleeding, such as epistaxis, ecchymosis, menorrhagia, and sometimes prolonged post-surgical bleeding. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] Platelet counts show moderate thrombocytopenia with an increase in mean platelet volume (MPV). Morphological analysis discloses giant platelets in variable proportions.…”

“…To date, 13 GP1BA variants 4–16 and 14 GP1BB variants, 15–22 considered to be responsible for monoallelic BSS, have been described in the literature (Table 1). 4–11,13–21,23 No variant responsible for monoallelic BSS has been identified to date in the GP9 gene.…”