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Rigshospitalet - a part of Copenhagen University Hospital
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The Copenhagen founder variant GP1BA c.58T>G is the most frequent cause of inherited thrombocytopenia in Denmark

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BACKGROUND: The classic Bernard-Soulier syndrome (BSS) is a rare inherited thrombocytopenia (IT) associated with severe thrombocytopenia, giant platelets, and bleeding tendency caused by homozygous or compound heterozygous variants in GP1BA, GP1BB, or GP9. Monoallelic BSS (mBSS) associated with mild asymptomatic macrothrombocytopenia caused by heterozygous variants in GP1BA or GP1BB may be a frequent cause of mild IT.

OBJECTIVE: We aimed to examine the frequency of mBSS in a consecutive cohort of patients with IT and to characterize the geno- and phenotype of mBSS probands and their family members. Additionally, we set out to examine if thrombopoietin (TPO) levels differ in mBSS patients.

PATIENTS/METHODS: We screened 106 patients suspected of IT using whole exome- or whole genome sequencing and performed co-segregation analyses of mBSS families. All probands and family members were phenotypically characterized. Founder mutation analysis was carried out by certifying that the probands were unrelated and the region around the variant was shared by all patients. TPO was measured by solid phase sandwich ELISA.

RESULTS: We diagnosed 14 patients (13%) with mBSS associated with heterozygous variants in GP1BA and GP1BB. Six unrelated probands carried a heterozygous variant in GP1BA (c.58T>G, p.Cys20Gly) and shared a 2.0 Mb region on chromosome 17, confirming that it is a founder variant. No discrepancy of TPO levels between mBSS patients and wild-type family members (P > .05) were identified.

CONCLUSION: We conclude that the most frequent form of IT in Denmark is mBSS caused by the Copenhagen founder variant.

Original languageEnglish
JournalJournal of thrombosis and haemostasis : JTH
Volume19
Issue number11
Pages (from-to)2884-2892
Number of pages9
ISSN1538-7933
DOIs
Publication statusPublished - Nov 2021

Bibliographical note

© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.

    Research areas

  • Bernard-Soulier Syndrome/diagnosis, Denmark, Homozygote, Humans, Pedigree, Platelet Glycoprotein GPIb-IX Complex/genetics, Thrombocytopenia/diagnosis

ID: 69933678