Bernard-Soulier Syndrome and Autosomal Dominant Macrothrombocytopenia via the GP1BB Gene

Bernard-Soulier syndrome (BSS) (OMIM 231200) (also sometimes called giant platelet syndrome) is a bleeding disorder characterized by mild to severe thrombocytopenia with large platelets. Onset is typically in infancy or childhood. Common bleeding problems include purpura, nose bleeds, gingival bleeding, and menorrhagia. BSS is caused by defects in the von Willebrand factor receptor on the platelet cell surface. Platelet-type or pseudo von Willebrand’s disease and benign Mediterranean macrothrombocytopenia are variants of BSS (Balduini et al. Haematologica 87:860-880, 2002). BSS is sometimes misdiagnosed as immune (idiopathic) thrombocytopenic purpura (ITP) (Kunishima et al. Eur J Haematol 76:348-355, 2006).

Bernard-Soulier syndrome (BSS) is an autosomal recessive disorder, although carriers of a single causative variant may have large platelets and mild bleeding problems. Occasionally, the symptoms in carriers are so strong that families display dominant inheritance (Savoia et al. Blood 97:1330-1335, 2001). The von Willebrand factor receptor has four glycoprotein (GP) subunits: GPIbα, GPIbβ, GPIX, and GPV encoded respectively by the GP1BA, GP1BB, GP9, and GP5 genes. Causative variants have been identified to date in all of these genes except GP5. Missense and nonsense variants predominate in cases of BSS, though small and large deletions and regulatory variants have also been reported in all BSS genes (see Lanza 2006). In addition, the Di George/velocardiofacial 22q11.2 deletions often include the GP1BB gene (see Budarf et al. Hum Mol Genet 4:763-766, 1995; and McDonald-McGinn et al.).

This test involves bidirectional DNA sequencing of the full coding regions of the GP1BB gene. About 20 bp of flanking non-coding DNA on either side of each exon are included. We will sequence the gene in relatives of affected children in cases where DNA from the children is unavailable. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known variants or to confirm research results.

Sensitivity of this test is unknown.  This test will not detect the deleted allele in patients carrying the DiGeorge/velocardiofacial 22q11.2 deletion.