The Copenhagen Founder Variant GP1BA C.58T>G is the Most Frequent Cause of Inherited Thrombocytopenia in Denmark

Overview

Journal J Thromb Haemost

Publisher Elsevier

Specialty Hematology

Date 2021 Aug 1

PMID 34333846

Citations 3

Authors

Eva Leinoe

Nanna Brons

Andreas Orslev Rasmussen

Migle Gabrielaite

Carlo Zaninetti

Raghavendra Palankar

Eva Zetterberg

Steen Rosthoj

Sisse Rye Ostrowski

Maria Rossing

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

GP1BB c.179C > T is the most frequent cause of monoallelic Bernard-Soulier syndrome in the Italian population after the Bolzano variant: a report of two new families.

Barozzi S, Pecci A, Marinoni M, Fontana G, Zanchetta M, Noris P Ann Hematol. 2022; 102(3):677-679.

PMID: 36539614 DOI: 10.1007/s00277-022-05079-0.

A Variant in a Czech Family with Monoallelic Bernard-Soulier Syndrome.

Skalnikova M, Stano Kozubik K, Trizuljak J, Vrzalova Z, Radova L, Reblova K Int J Mol Sci. 2022; 23(2).

PMID: 35055070 PMC: 8777725. DOI: 10.3390/ijms23020885.

The Copenhagen founder variant GP1BA c.58T>G is the most frequent cause of inherited thrombocytopenia in Denmark.

Leinoe E, Brons N, Rasmussen A, Gabrielaite M, Zaninetti C, Palankar R J Thromb Haemost. 2021; 19(11):2884-2892.

PMID: 34333846 PMC: 9292710. DOI: 10.1111/jth.15479.

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