Analysis of the genotypes and phenotypes of 37 unrelated patients with inherited factor VII deficiency

Severe inherited factor VII (FVII) deficiency is a rare autosomal recessive disorder with a poor relationship between FVII coagulant activity and blee ding tendency. Both clinical expression and mutational spectrum are highly variable. We have screened for mutations the FVII gene of 37 unrelated pati ents with a FVII coagulant activity less than 5% of normal pooled plasmas. The nine exons with boundaries and the 5' flanking region of the FVII gene were explored using a combination of denaturing gradient gel electrophoresi s and direct DNA sequencing. This strategy allowed us to characterise 68 ou t of the 74 predicted FVII mutated alleles. They corresponded to a large pa nel of 40 different mutations. Among these, 18 were not already reported. G enotypes of the severely affected patients comprised, on both alleles, dele terious mutations which appeared to be related to a total absence of activa ted FVII. We suggest that this absence of functional FVII can explain the s evere clinical expression. Whether a small release of FVII is sufficient to initiate the coagulation cascade and to prevent the expression of a severe phenotype, requires further investigations.