Familial Bernard-Soulier Syndrome Due to a Novel Ins/Del Mutation in Glycoprotein IX.
Authors: Cutler Jacky , Mitchell Mike , Goubran Hady , Savidge Geoffrey F. 
Published: October 2019

Abstract
Bernard-Soulier syndrome (BSS) is a rare autosomal recessive bleeding problem, characterised by thrombocytopaenia, large dysfunctional platelets, and defective von-Willebrand factor dependent platelet aggregation. It is caused by a qualitative or quantitative abnormality of the platelet glycoprotein (GP) 1b/IX/V complex. Of the components of this complex, defects have been identified in all but GPV; in order of frequency of mutation GP1bα >GPIX >GP1bβ. Classically, mutations in any of these chains will lead to a total absence of the complex from the platelet surface, but variant forms of BSS have been described in which there is an inbalance in the expression of GPIX in relation to GP1b and GPV chains.
We present a case study of a familial BSS. The proband was originally referred to this centre with a diagnosis of probable type 3 von Willebrand disease. He presented with lifelong epistaxis and oral bleeding, which have been variously treated with whole blood, F8 concentrate and platelet transfusion. Two unrelated surgical procedures were uneventful. Laboratory investigations showed a platelet count of 22 x109 /L, normal vWF antigen, activity and collagen binding, and abnormal platelet function screens in the presence of both ADP and epinephrine. Platelet glycoprotein analysis by FACs failed to detect any expression of GP1bα, GP1bβ or GPIX. Following these laboratory investigations the diagnosis was amended to BSS. The patient is the eldest of five children of consanguinous (first cousin) parents of Egyptian origin. One sister has a bleeding diathesis of approximately equal severity to the proband. The mother and another sister presented with much less pronounced bleeding. The remaining family members are asymptomatic; however, one sister is pre-pubescent, and may present with menorraghia in the future.
Genetic analysis of the GP1bα, GP1bβ and GPIX genes was undertaken in the proband, and a novel ins/del mutation identified in the only coding exon of GPIX. Nucleotides 1717–1721 (TGTAC) are replaced with alternate bases (GTGGG) of unknown origin. This mutation results in the replacement of cysteine-8 and threonine-9 with valine -8 and glycine-9. The loss of the cysteine residue at codon 8 disrupts a putative disulphide bond between cysteine-8 and cysteine -12, thereby impairing correct assembly and anchoring of GPIX on the platelet surface. Mutations affecting the conserved cysteine residues of each subunit of the GP1b/IX complex have been reported, and have a significant effect on the biosynthesis and function of the complex.
Analysis of family members determined that both parents, and two siblings are heterozygous for this mutation, while the equally symptomatic sister and the youngest child are homozygous.
Heterozygosity for this novel ins/del mutation is unlikely to explain the mild bleeding diathesis seen in some female members of this family. Phenotypic investigations are ongoing, but thus far have proved inconclusive in demonstrating a coexisting haemostatic disorder, such as type 1vWD or mild FVII deficiency.