Abstract Number: PB0866
Meeting: ISTH 2021 Congress
Background: Heterozygous carriers of Bernard-Soulier syndrome (BSS) often have normal platelet counts. However, BSS can be inherited as an autosomal dominant trait associated with mild macrothrombocytopenia.
Aims: We present the results of genetic, phenotypic and co-segregation analyses of fourteen families with monoallelic BSS (mBSS).
Methods: DNA was analyzed by whole genome sequencing (WGS). A flow cytometric diagnosis of mBSS using Kaluza Flow Cytometry Software v. 2.1 (Beckman Coulter) was made by calculating the ratio between median expressions of CD42b and CD41a in percentages of healthy subjects. Identity by descent of the genomes was estimated with PLINK 1.9 after initial pruning of sites in linkage disequilibrium. Thrombopoietin (TPO) concentrations were analyzed by a commercially available solid phase sandwich ELISA test.
Results: We analyzed 106 patients referred for inherited thrombocytopenia (IT) by WGS and identified fourteen probands suspected of mBSS associated macrothrombocytopenia (13%). Peripheral blood smears from the probands demonstrated macrothrombocytes and the relative ratio of CD42b/CD41a was < 1 (median 0.52, range 0.40 – 0.67). Co-segregation analyses were performed among 46 family members whereof 31 patients carried a heterozygous variant associated with mBSS. Median platelet count was 91 x 109/L (range 44-131). We found significant ISTH BAT scores in two of the fourteen probands. Six probands carried the same heterozygous variant in GP1BA (c.58T>G, p.Cys20Gly). No cryptic relatedness was found across their genomes, and they shared a 2.0 Mb region on chromosome 17. The c.58T>G variant likely prevents the formation of the disulfide bond between Cys20 and Cys33, thereby disrupting the local stability of the protein secondary structure. TPO levels in patients were normal (median 16.5 AU/ml), not significantly different (p>0.05) from family members with wild type (median 17 AU/ml).
Conclusions: Monoallelic BSS is the most frequent form of IT in the Copenhagen Region and this may be due to a founder variant in GP1BA (c.58T>G, p.Cys20Gly).
To cite this abstract in AMA style:Leinøe E, Broens N, Rasmussen AO, Gabrielaite M, Rosthoej S, Zetterberg E, Ostrowski SR, Rossing M. The Copenhagen Founder Variant GP1BA c.58T>G is Causal of Monoallelic Bernard-Soulier Syndrome [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/the-copenhagen-founder-variant-gp1ba-c-58tg-is-causal-of-monoallelic-bernard-soulier-syndrome/. Accessed November 29, 2021.
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