Mutations in the fibrinogen aalpha gene account for the majority of cases of congenital afibrinogenemia.
Congenital afibrinogenemia is a rare, autosomal, recessive disorder characterized by the complete absence of detectable fibrinogen. We previously identified the first causative mutations in a nonconsanguineous Swiss family; the 4 affected persons have homozygous deletions of approximately 11 kb of the fibrinogen alpha (FGA) gene. Haplotype data implied that these deletions occurred on distinct ancestral chromosomes, suggesting that this region may be susceptible to deletion by a common mechanism. We subsequently showed that all the deletions were identical to the base pair and probably resulted from a nonhomologous recombination mediated by 7-bp direct repeats. In this study, we have collected data on 13 additional unrelated patients to identify the causative mutations and to determine the prevalence of the 11-kb deletion. A common recurrent mutation, at the donor splice site of FGA intron 4 (IVS4 + 1 G > T), accounted for 14 of the 26 (54%) alleles. One patient was heterozygous for the previously identified deletion. Three more frameshift mutations, 2 nonsense mutations, and a second splice site mutation were also identified. Consequently, 86% of afibrinogenemia alleles analyzed to date have truncating mutations of FGA, though mutations in all 3 fibrinogen genes, FGG, FGA, and FGB, might be predicted to cause congenital afibrinogenemia.