A Novel Homozygous c.800C>G Substitution in <b><i>GP1BA</i></b> Exon 2 in a Kuwaiti Family with Bernard-Soulier Syndrome

Abstract

Background: Bernard-Soulier syndrome (BSS) is a congenital bleeding disorder characterised by thrombocytopenia, giant platelets and decreased platelet adhesion resulting from genetic alterations of the glycoprotein (GP) Ib/IX/V complex. Objectives: Three sisters with a lifelong bleeding history and a provisional diagnosis of BSS were referred for further characterisation of their bleeding diathesis. The siblings' symptoms varied in severity from skin and gum bleeding to menorrhagia associated with iron-deficiency anaemia requiring regular transfusion of red cells and platelets. The parents were consanguineous but did not demonstrate any bleeding disorder. Methods: The family were investigated using standard haematological techniques, platelet aggregometry, platelet membrane GP analysis and DNA sequencing of the genes encoding the GPIb/IX complex. Results: All 3 sisters had thrombocytopenia and giant platelets. Platelet aggregation and flow cytometry studies confirmed the lack of aggregation with ristocetin and a markedly reduced GPIb/IX surface expression. Molecular analysis demonstrated a novel homozygous c.800C>G substitution in GP1BA exon 2 leading to a serine 267 Ter stop codon in all 3 siblings. Conclusions: A novel, nonsense mutation was identified as the cause of the bleeding disorder in this family. This is the first reported BSS mutation identified in a family from Kuwait.

Menstrual and obstetrical bleeding in women with inherited platelet receptor defects—A systematic review

“…One hundred and thirty‐two articles were examined in full text, of which 69 were eventually included in this systematic review. These comprised 61 case reports and series and eight cohort studies . The exact number of women with HMB is uncertain due to incomplete reporting in one article .…”

Identification of mutations in SLC4A1, GP1BA and HFE in a family with venous thrombosis of unknown cause by next‑generation sequencing

“…Mutations within the leucine-rich repeat C-terminal domain of GP1BA (p.Asp235Tyr, p.Trp246Leu or p.Met255Ile) may cause platelet-type von Willebrand disease (24)(25)(26). The association between genetic disorders of GP1BA and Bernard-Soulier syndrome (also known as giant platelet syndrome), which is characterized by a low platelet count and giant platelets, has been reported in Iranian, Indian and Kuwaiti populations, even though the gene variants or frameshifts are located in different regions of the GP1BA sequence (27)(28)(29)(30). Furthermore, a GP1BA polymorphism has been associated with post-partum hemorrhage (31).…”