title: Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations.
abstract: BACKGROUND
  Bernard-Soulier syndrome is a severe bleeding disease due to a defect of GPIb/IX/V, a platelet complex that binds the von Willebrand factor. Due to the rarity of the disease, there are reports only on a few cases compromising any attempt to establish correlations between genotype and phenotype. In order to identify any associations, we describe the largest case series ever reported, which was evaluated systematically at the same center.
  
  
  METHODS
  Thirteen patients with the disease and seven obligate carriers were enrolled. We collected clinical aspects and determined platelet features, including number and size, expression of membrane glycoproteins, and ristocetin induced platelet aggregation. Mutations were identified by direct sequencing of the GP1BA, GP1BB, and GP9 genes and their effect was shown by molecular modeling analyses.
  
  
  RESULTS
  Patients all had a moderate thrombocytopenia with giant platelets and a bleeding tendency whose severity varied among individuals. Consistent with expression levels of GPIbα always lower than 10% of control values, platelet aggregation was absent or severely reduced. Homozygous mutations were identified in the GP1BA, GP1BB and GP9 genes; six were novel alterations expected to destabilize the conformation of the respective protein. Except for obligate carriers of a GP9 mutation with a reduced GPIb/IX/V expression and defective aggregation, all the other carriers had no obvious anomalies.
  
  
  CONCLUSIONS
  Regardless of mutations identified, the patients' bleeding diathesis did not correlate with thrombocytopenia, which was always moderate, and platelet GPIbα expression, which was always severely impaired. Obligate carriers had features similar to controls though their GPIb/IX/V expression showed discrepancies. Aware of the limitations of our cohort, we cannot define any correlations. However, further investigations should be encouraged to better understand the causes of this rare and underestimated disease.
authors.affiliation: Department of Reproductive and Developmental Sciences and Public Medicine Sciences, University of Trieste, Trieste, Italy. savoia@burlo.trieste.it
authors.forename: Anna
authors.initials: A
authors.lastname: Savoia
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pastore
authors.forename: Daniela
authors.initials: D
authors.lastname: De Rocco
authors.forename: Elisa
authors.initials: E
authors.lastname: Civaschi
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Di Stazio
authors.forename: Roberta
authors.initials: R
authors.lastname: Bottega
authors.forename: Federica
authors.initials: F
authors.lastname: Melazzini
authors.forename: Valeria
authors.initials: V
authors.lastname: Bozzi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pecci
authors.forename: Silvana
authors.initials: S
authors.lastname: Magrin
authors.forename: Carlo L
authors.initials: CL
authors.lastname: Balduini
authors.forename: Patrizia
authors.initials: P
authors.lastname: Noris
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001606:Bernard-Soulier Syndrome / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D001792:Blood Platelets / Q000473:pathology; D048430:Cell Shape; D002648:Child; D002675:Child, Preschool; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers; D006470:Hemorrhage; D006720:Homozygote; D006801:Humans; D007558:Italy; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis* / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D010974:Platelet Aggregation / Q000187:drug effects; D010976:Platelet Count; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012310:Ristocetin / Q000494:pharmacology; D013921:Thrombocytopenia / Q000097:blood; D055815:Young Adult; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D005819:Genetic Markers; D008562:Membrane Glycoproteins; D019038:Platelet Glycoprotein GPIb-IX Complex; C094990:adhesion receptor; D014841:von Willebrand Factor; D012310:Ristocetin