Deletion of the fibrogen alpha-chain gene (FGA) causes congenital afibrogenemia

Congenital afibrinogenemia is a rare autosomal recessive disorder character ized by the complete absence of detectable fibrinogen. Uncontrolled bleedin g after birth from the umbilical cord is common, and spontaneous intracereb ral bleeding and splenic rupture can occur throughout life. Patients respon d well to fibrinogen replacement therapy, either prophylactically or on dem and. Because the half-life of infused fibrinogen is essentially normal, the genetic defect is assumed to be at the level of synthesis, but no responsi ble locus has been identified. Preliminary studies using Southern blotting suggested that no gross structural changes of the fibrinogen genes were pre sent in patients. We report the identification of causative mutations in a nonconsanguineous Swiss family with congenital afibrinogenemia. The four af fected male individuals (two brothers and their two first cousins) have hom ozygous deletions of similar to 11 kb of the fibrinogen alpha-chain gene (F GA) Haplotype data suggest that these deletions occurred separately, on thr ee distinct ancestral chromosomes, implying that the FGA region of the fibr inogen locus is susceptible to deletion by a common mechanism. Furthermore, our results demonstrate that humans, like mice, may be born without the ca pacity to synthesize functional fibrinogen.