Mutations in the fibrinogen A alpha gene account for the majority of casesof congenital afibrinogenemia

Congenital afibrinogenemia is a rare, autosomal, recessive disorder charact erized by the complete absence of detectable fibrinogen. We previously iden tified the first causative mutations in a nonconsanguineous Swiss family; t he 4 affected persons have homozygous deletions of approximately 11 kb of t he fibrinogen alpha (FGA) gene. Haplotype data implied that these deletions occurred on distinct ancestral chromosomes, suggesting that this region ma y be susceptible to deletion by a common mechanism. We subsequently showed that all the deletions were identical to the base pair and probably resulte d from a nonhomologous recombination mediated by 7-bp direct repeats. In th is study, we have collected data on 13 additional unrelated patients to ide ntify the causative mutations and to determine the prevalence of the 11-kb deletion. A common recurrent mutation, at the donor splice site of FGA intr on 4 (IVS4 + 1 G > T), accounted for 14 of the 26 (54%) alleles, One patien t was heterozygous for the previously identified deletion. Three more frame shift mutations, 2 nonsense mutations, and a second splice site mutation we re also identified. Consequently, 86% of afibrinogenemia alleles analyzed t o date have truncating mutations of FGA, though mutations in all 3 fibrinog en genes, FGG, FGA, and FGB, might be predicted to cause congenital afibrin ogenemia. (Blood. 2000;96:149-152) (C) 2000 by The American Society of Hema tology.