PB0713 - Extensive Genetic Screening of Iranian FVII deficient Individuals with severe phenotype unraveled Several Novel Mutations

Background: Coagulation factor VII (FVII) deficiency (OMIM: 227500) is the most common rare bleeding disorder characterized by low or undetectable plasma levels of FVII, a key player in the initiation of blood coagulation. Mutations that result in the complete absence of active protein are associated with early onset pathologies such as neonatal mortality or irreversible organ damage such as intracranial hemorrhage (ICH), defined as severe phenotype. In several cases, a discrepancy between the FVII activity (FVII:C) levels and the observed phenotype has been reported while the underlying reason is largely elusive.

Aims: The aim of the present study was to identify molecular defects that might be related to neonatal and infantile bleeding in phenotypically severe FVII deficient patients.

Methods: 24 independent pedigrees with at least one individual presenting severe phenotype are recruited for genetic analysis using standard PCR-Sanger sequencing. For a few cases, whole-exome sequencing was also performed for in-depth genetic analysis. The study was conducted in accordance with the Helsinki Declaration and approved by Zanjan University of Medical Sciences Ethics Committee (IR.ZUMS.REC.1398.280)

Results: 9 homozygote mutations were identified in 24 individuals with severe phenotype of which c.1A>G (Met1Val), c.634C>T (Arg212Stop) and c.1285G>A (Ala429Thr) were previously reported in heterozygotes. Homozygous c.790delC was identified in 8 independent pedigrees of similar ethnicity. Presence of a founder effect is therefore suggested for this gene alteration.

Conclusion(s): The mutations we report here not only enrich the current database of FVII patients and mutations (https://f7-db.eahad.org/), but clarify the critical role of certain amino acids in FVII protein seq. which their homozygote modification will be disastrous.