Molecular pathology of Bernard-Soulier syndrome in Indian patients

Bernard-Soulier syndrome (BSS) is an extremely rare form of platelet adhesion disorder caused by genetic changes occurring in the glycoprotein genes GPIb alpha, GPIb beta and GPIX with autosomal recessive inheritance pattern. Eight patients from seven unrelated families from Western India were included in this study. Diagnosis of BSS was based on low platelet count, presence of giant platelets in peripheral smear, normal screening coagulation tests, reduced or absence of platelet response to ristocetin in aggregometry studies and reduced or lack of expression of GPIb/IX/V complex on platelet surface in flow cytometry studies. Genomic DNA was screened for mutations in GPIb alpha, GPIb beta and GPIX using direct sequencing method. Six disease causing mutations were detected, out of which four were novel changes including one nonsense (p.Cys32X) in two patients and two missense (p.Tyr95Asp and p.Cys135Tyr) changes in GPIX gene, one insertion mutation (p.Met338fsX13) in GPIb alpha gene resulting in a frameshift change and two reported mutations, i.e. one insertion mutation in GPIb alpha gene (p.Val485fsX13) resulting in a new termination codon and one missense change (p.Cys24Arg) in two patients in GPIX gene. The molecular basis of BSS patients presented here shows the heterogeneity of this disorder in Indian patients besides providing a basis for genetic diagnosis of affected families.