Novel Mutation in the Glycoprotein Ibβ in a Patient with Bernard-Soulier Syndrome: Possibility of Distant Parental Consanguinity

Bernard-Soulier syndrome (BSS) is a rare autosomal recessive disorder characterized by a prolonged skin-bleeding time and thrombocytopenia with giant platelets. The hallmark of BSS is an abnormal platelet attachment to the vessel wall due to reduced or abnormal glycoprotein (GP) Ib/IX/V complex. We present a case of BSS in a 14-month-old boy caused by a novel genetic mutation.

A 14-month-old Syrian boy was referred to our medical center with a history of easy bruisability, epistaxis, and low platelet counts since the age of 5 months. He was the second child of non-consanguineous parents. His parents and siblings were negative for a history of bleeding disorders. His nephew was reported to have low platelets counts. The patient was hospitalized in Syria several times and was initially diagnosed as having idiopathic thrombocytopenic purpura. He received corticosteroids and high-dose intravenous immunoglobulin both of which were ineffective. He also received platelet transfusion for recurrent epistaxis, which improved as per the parents. The possibility of a platelet disorder was raised and he was referred to our center for further investigation.

Physical examination showed bruises over the face and extremities. Abdominal examination was negative for hepatosplenomegaly. There were no congenital abnormalities. His platelet count was 100 × 10⁹/l. The presence of giant platelets was noted on blood film inspection. Other blood cell counts, blood chemistry and coagulation studies, including von Willebrand factor (vWF) antigen and activity, were within the normal range. A clinical diagnosis of BSS was made. Peripheral blood was obtained for genetic testing.

DNA sequencing and analysis

The initial extraction of the DNA material was done using the PEL-FREEZ extraction kit (PEL-FREEZ, DYNAL, USA) and genomic material stored at −80°C. We performed direct sequencing of the entire coding regions including exon-intron boundaries of the GPIbα and GPIbβ genes (GenBank: NM_000173.5 and NM_000407.4; mutation numbering + 1 corresponds to the A of the ATG-translation initiation codon, respectively). Genomic DNA from patient was amplified by PCR with oligonucleotide primers complementary to flanking intronic sequences. Primers were designed using the Primer3 program (http://www-genome.wi.mit.edu/cgi-bin/primer/primer3.cgi) (primer sequences and PCR conditions are available on request). PCR products were sequenced employing ABI BigDye chemistry (Applied Biosystems, Darmstadt, Germany). The same primers as for PCR were used as sequencing primers. Samples were run and analyzed on an ABI PRISM 3130 genetic analyzer (Applied Biosystems).

We present a case of BSS in a 14-month-old boy caused by a novel nonsense mutation (c.423C>A) in the GPIbβ gene. Knowing that we are dealing with a very rare syndrome, the detected mutation in our patient was homozygous. Although the parents were non-consanguineous, we believe that they were related in a distant parental consanguinity which the parents and their family were not aware of.

No relevant conflicts of interest to declare.