Impact of a new genetic variant on FVII: C activity

Background: The prediction of the phenotypic effect of a genetic variant represents a useful tool in genetic counseling. However, in coagulation factor VII (FVII) deficiency there is no straight correlation between genotype and phenotype since the residual FVII coagulant (FVII:C) activity associated with specific genetic variants does not always account for the observed clinical signs. Objective: to better describe the correlation between genotype and clinical phenotype of F7 gene we report a family case with a deficient FVII:C activity. Results and discussion: The case under investigation came to our attention during a genetic counseling attended by the proband, because she wanted to know, given the familiarity for breast cancer, her carrier probability for a BRCA1/2 pathogenetic variant. Pedigree analysis showed that besides cancer predisposition both the proband and her two sons suffered from recurrent spontaneous bleeding. Their coagulation pathway analysis was indicative of a FVII:C activity reduction with a pattern mimicking an autosomal dominant inheritance. Proband F7 sequencing showed the following heterozygous variants: c.1088C>A (p.Pro363His), c.-326_-325insCCTATATCC, c.-122T>C and c.1238G>A. The molecular analysis of her sons highlighted that c.1088C>A variant was in trans configuration. The occurrence of c.1088C>A variant alone was associated with 36% of FVII:C residual activity. Conversely, when this variant was in compound heterozygosity with c.-326_-325insCCTATATCC, c.-122T>C and c.1238G>A haplotype, the FVII:C residual activity further shrinked to 22%. c.1088C>A variant alone determined the most significant FVII:C activity reduction, however, when found in combination with c.-326_-325insCCTATATCC, c.122T>C and c.1238G>A haplotype an additive effect on the FVII:C activity phenotype was observed.