A Novel Disease-causing Variant in the GP1BA Gene Related to Bernard Soulier Syndrome

ALBERTO MF; ASENSIO M; SANCHEZ LUCEROS ANALIA; WOODS AI; PAIVA J; BLANCO AN; PRIMROSE, DEBORA M.; CASINELLI MM

Philadelphia

Congreso; ISTH 2021 VIRTUAL CONGRESS; 2021

International Society on Thrombosis and Haemostasis

Background: Bernard Soulier syndrome (BSS) is a rare autosomal bleedingdisorder caused by homozygous or compound heterozygous disease-causingvariants (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 isrecessive (biallelic) with severe bleeding and moderate macrothrombocytopenia.Heterozygous patients are usually asymptomatic with Slight macrothrombocytopenia, reduced GPIb-IX-V expression, slightly reducedristocetin-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 factorFVIII: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 specificmonoclonal antibodies (CD42b, CD41 and CD61).Genomic DNA was extracted from peripheral blood. GP1BA was amplified by PCRand sequenced (Sanger methodology).Genome Aggregation Database, Human Gene Mutation Database, Leiden OpenVariation Database and Varsome were accessed to check the registry of variants.Results: Male (56-yrs) (ISTH-SSC-BAT=0) was evaluated after obtaining writteninformed consent. He showed reduced platelets count (121×10 /L),macroplatelets (mean platelet volume=10.9fL; normal-range=7-10.5fL),1.2mg/mL-RIPA=slightly normal with latency period, normal plateletaggregation, clotting and fibrinolytic systems.Flow-cytometry: 50% of expression with CD42b; normal expression with bothCD41 and CD61.GP1BA sequence analysis: a novel missense substitution c.692A>G→p.Tyr231Cysin heterozygocity, predicted as damaging by PolyPhen-2, SIFT, Mutation-Taster,Provean and Varsome. I-Mutant predicted p.Tyr231Cys as large decrease ofstability; p.Tyr231Cys was not found in 100 controls, without entries in thevariant databases and was deposited in the LOVD at http://www.lovd.nl/GP1BA.Conclusions: We report a patient with no bleeding symptpms, mildmacrothrombocytopenia, 50% of GPIb expression and heterozygous p.Tyr231Cysin the GP1BA, with negative effect influencing in both platelet count and size andin the expression of the GPIb. It appears to show recessive