Abstract Number: PB0904
Meeting: ISTH 2021 Congress
Background: Bernard Soulier syndrome (BSS) is a rare autosomal bleeding disorder caused by homozygous or compound heterozygous disease-causing variants (DCV) in any of the genes encoding for glycoprotein-Ib (GPIb) (GP1BA, GP1BB) and GPIX (GP9) of the platelet GPIb-IX-V-complex. The typical form is recessive (biallelic) with severe bleeding and moderate macrothrombocytopenia.
Heterozygous patients are usually asymptomatic with slight macrothrombocytopenia, reduced GPIb-IX-V expression, slightly reduced ristocetin-induced platelet aggregation (RIPA), and considered BSS carriers.
Aims: To describe a novel DCV responsible for recessive BSS.
Methods: Tests performed: platelet count; coagulation profile including factor FVIII:C; VWF:Ag; VWF:RCo; platelet aggregation (2μM-ADP, 1μM-epinephrine, 1μg/mL-collagen and 1mM-arachidonic acid).
GPIb-IX and GPIIb-IIIa expression was analyzed by flow-cytometry using specific monoclonal antibodies (CD42b, CD41 and CD61).
Genomic DNA was extracted from peripheral blood. GP1BA was amplified by PCR and sequenced (Sanger methodology).
Genome Aggregation Database, Human Gene Mutation Database, Leiden Open Variation Database and Varsome were accessed to check the registry of variants.
Results: Male (56-yrs) (ISTH-SSC-BAT=0) was evaluated after obtaining written informed consent. He showed reduced platelets count (121×109/L), macroplatelets (mean platelet volume=10.9fL; normal-range=7-10.5fL), 1.2mg/mL-RIPA=slightly normal with latency period, normal platelet aggregation, clotting and fibrinolytic systems.
Flow-cytometry: 50% of expression with CD42b; normal expression with both CD41 and CD61.
GP1BA sequence analysis: a novel missense substitution c.692A>G→p.Tyr231Cys in heterozygocity, predicted as damaging by PolyPhen-2, SIFT, Mutation-Taster, Provean and Varsome. I-Mutant predicted p.Tyr231Cys as large decrease of stability; p.Tyr231Cys was not found in 100 controls, without entries in the variant databases and was deposited in the LOVD at http://www.lovd.nl/GP1BA.
Conclusions: We report a patient with no bleeding symptpms, mild macrothrombocytopenia, 50% of GPIb expression and heterozygous p.Tyr231Cys in the GP1BA, with negative effect influencing in both platelet count and size and in the expression of the GPIb. It appears to show recessive inheritance for BSS.
This patient was diagnosed as carrier of BSS.
To cite this abstract in AMA style:Woods AI, Alberto MF, Primrose DM, Paiva J, Asencio M, Casinelli MM, N Blanco A, Sánchez-Luceros A. A Novel Disease-causing Variant in the GP1BA Gene Related to Bernard Soulier Syndrome [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/a-novel-disease-causing-variant-in-the-gp1ba-gene-related-to-bernard-soulier-syndrome/. Accessed August 16, 2022.
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