Abstract Number: PB1449
Meeting: ISTH 2020 Congress
Background: Inherited thrombocytopenias (ITs) are rare diseases displaying low platelet count and high heterogeneity. Nowadays, mutations in more than 30 different genes are known to cause IT, but they account for approximately 50% of the patients.
Bernard-Soulier syndrome (BSS) is an IT characterized by defects of GPIb-IX-V complex, the platelets’ von Willebrand factor receptor. BSS occurs in two forms: biallelic severe and monoallelic moderate. Most of the mutations identified in the BSS genes (GP1BA, GP1BB, GP9) prevent the complex expression; consequently, platelets are defective to adhere to the vascular subendothelium.
Aims: Our work is aimed at understanding the role of the BSS variants identified by NGS, as disease-causing mutations.
Methods: We applied NGS analysis to identify mutations in our cohort of IT families (N=141). After cloning wild type and mutant GP1BA cDNA into an expression vector, protein level was evaluated both by western blot and flow cytometry.
Results: We found more than 20 rare variants that could be categorized as causative of biallelic (N=4) or monoallelic forms of BSS (N=20), but also heterozygous variants (N=10) of uncertain significance that could explain a series of ITs cases. The frequency of the variants identified in our cohort is higher than in the general population, moreover, most of them are novel missense substitutions. Focusing on the GP1BA gene, we found that the overexpressed mutant proteins are differently stable and/or expressed on cellular membrane, suggesting the pathogenetic role of some of them.
Conclusions: Our work extends the spectrum of mutations identified in BSS genes, underlying the importance of genetic testing in recognizing both monoallelic and biallelic forms of BSS. Moreover, we have identified private candidate variants that could be associated with the BSS monoallelic. Once confirmed their effect on GPIb-IX-V receptor, we could be able to explain thrombocytopenia in almost 5% of the cases without a molecular diagnosis.
To cite this abstract in AMA style:Fontana G, Giangregorio T, De Rocco D, Valencic E, Noris P, Barozzi S, Bozzi V, Balduini C, Pecci A, Lanza F, Savoia A. Bernard – Soulier Syndrome (BSS): From Identification of the Variants to their Functional Studies [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/bernard-soulier-syndrome-bss-from-identification-of-the-variants-to-their-functional-studies/. Accessed September 21, 2023.
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