Mild haemophilia A in Iceland: clinical genetic studies of three families with the same mutation

Abstract

OBJECTIVES: The aim of the study was to define the phenotype in three families with mild haemophilia A and to determine restriction fragment length polymorphisms (RFLP), which could support a hypothesis of a common progenitor of the families. DESIGN: Family survey. SETTING: Index cases were identified in and outside hospital and a family survey for symptoms and signs of bleeding in family members and sampling for coagulation and RFLP studies were mostly carried out in the field. SUBJECT: Family members with and without symptoms of bleeding were selected for investigation and normal spouses and unrelated individuals were investigated for control. INTERVENTIONS: Medical advice regarding affected family members were given to the families and their physicians. MAIN OUTCOME MEASURES: Bleeding time, factor VIII activity, quantification of factor VIII:Ag, von Willebrand factor (vWF) Ag and vWF ristocetin assay. Typing of RFLP polymorphisms for genetic homogeneity. RESULTS: Bleeding manifestations are present in both sexes in the three families although more frequent and more severe in the males. The level of factor VIII activity is between 10 and 20% in most affected males whereas 35-60% is found approximately in 2/3 of female carriers and in 1/3 of them factor VIII activity is within the normal range. It is suggested that screening for this mild haemophilia A gene by a molecular genetic method would be of clinical value now, its mutation having been detected. CONCLUSIONS: Transmission of mild haemophilia A through six to seven generations is demonstrated by the study. The mild haemophilia A type described is the most prevalent of haemophilia A types in Iceland (population 260,000, 1992). The founder effect was confirmed by studies of RFLP polymorphisms