Novel Compound Heterozygous Mutations in Two Families With Bernard–Soulier Syndrome

Milen Minkov,Milen Minkov,Milen Minkov,Andreas Zoubek,Oskar A Haas,Oskar A Haas,Leo Kager,Leo Kager,Petra Zeitlhofer,Simon Panzer

doi:10.3389/fped.2020.589812

Milen Minkov, Milen Minkov + Show 8 more

Open Access

https://doi.org/10.3389/fped.2020.589812

Copy DOI

Abstract

Background: Bernard–Soulier Syndrome (BSS) is a rare autosomal recessive bleeding disorder with large platelets and thrombocytopenia. It is caused by homozygous or compound heterozygous mutations in the GP1BA, GP1BB, or GP9 genes, which together encode the platelet surface receptor glycoprotein complex GPIb-IX-V.Objectives: We report two novel heterozygous mutations in the GP1BA and the GP9 genes, respectively.Patients/Methods: We analyzed the platelet glycoprotein expression by flow cytometry and screened the relevant genes for responsible mutations in two unrelated families.Results: Flow cytometric analyses revealed the absence of CD42a (GPIX) and CD42b (GPIb) on the platelets in the two affected siblings of family 1 and a significantly reduced expression of CD42b (GPIb) in the patient of family 2. In the two siblings, we identified a known frameshift (c.1601_1602delAT) and a novel nonsense mutation (c.1036C>T) in the GP1BA gene that abrogated the production of GP1bα. In the other patient, we found a novel missense mutation (c.112T>C) that was co-inherited with a common one (c.182A>G) in the GP9 gene, respectively. All analyzed heterozygous carriers were asymptomatic and had a normal GPIb-IX-V expression.Conclusions: The two novel GP1BA and GP9 mutations reported herein increment the number of causative genetic defects in BSS.

Highlights

Bernard–Soulier Syndrome (BSS; OMIM ID #231200), is a rare autosomal recessive inherited bleeding disorder that is characterized by thrombocytopenia and large platelets [1, 2]
The bleeding tendency in BSS results from the functional impairment of the glycoprotein complex Ib-IX-V (GPIb-IX-V), which consists of four polypeptide chains (GPIbα, GPIbβ, GPIX, and GPV) that are assembled in a ratio of 2:4:2:1 [3,4,5]
Homozygous or compound heterozygous mutations in GP1BA, GP1BB, or GP9 genes are responsible for the autosomal recessive forms and mutations in the GP1BA gene for the rare autosomal dominant trait [6,7,8,9], whereas none are known in the GP5 gene [10]

Summary

Introduction

Bernard–Soulier Syndrome (BSS; OMIM ID #231200), is a rare autosomal recessive inherited bleeding disorder that is characterized by thrombocytopenia and large platelets [1, 2]. The four polypeptide chains are coded by the genes GP1BA, GP1BB, GP9, and GP5, respectively. We report three compound heterozygous BSS cases from two families in which we identified two novel mutations in the GP1BA and the GP9 genes, respectively. Bernard–Soulier Syndrome (BSS) is a rare autosomal recessive bleeding disorder with large platelets and thrombocytopenia. It is caused by homozygous or compound heterozygous mutations in the GP1BA, GP1BB, or GP9 genes, which together encode the platelet surface receptor glycoprotein complex GPIb-IX-V

Objectives

Methods

Results

Conclusion