F7 – Congenital Factor VII Deficiency

Autosomal recessive variants in the F7 gene (HGNC:3544) underlie congenital factor VII deficiency (MONDO:0009211), a rare bleeding disorder characterized by isolated prolonged prothrombin time (HP:0008151). F7 encodes the vitamin K–dependent serine protease factor VII, which, upon activation to factor VIIa, initiates the extrinsic coagulation cascade via tissue factor binding. Patients present with a broad phenotypic spectrum, from asymptomatic laboratory findings to life‐threatening intracranial hemorrhage.

Clinical Validity

The gene–disease association is classified as Definitive based on over 123 unrelated probands with biallelic F7 variants in cohort studies and extensive segregation data across multiple families. Segregation of pathogenic alleles in at least 7 affected relatives supports autosomal recessive inheritance and cosegregation of disease (PMID:7974346, PMID:28447100).

Genetic Evidence

Inheritance is Autosomal recessive, with 7 affected relatives showing co‐segregation of deleterious alleles. Case series and large genotype–phenotype studies report 123 probands with F7 variants including missense, splice‐site, promoter, and frameshift mutations (PMID:28447100). Variant spectrum comprises predominantly missense substitutions (~62%), large deletions (~6%), and promoter defects. Recurrent alleles such as c.911G>A (p.Arg304Gln) and hotspots in exon 9 underscore population‐specific founder effects.

Functional / Experimental Evidence

Mechanisms include protein misfolding and impaired secretion, leading to type I deficiency (concomitant low antigen and activity), and defective tissue factor binding in type II forms. In vitro expression of FVII missense mutants (e.g., c.1325del (p.Pro442fs), c.995C>T (p.Ala332Val), c.413A>G (p.Gln138Arg)) provokes endoplasmic reticulum stress and unfolded protein response, with reduced secretion and activity in CHO and HEK293 cells (PMID:29618153, PMID:22628013).

Phenotypic Spectrum & Management

Clinical manifestations range from epistaxis, menorrhagia, and gum bleeding to severe intracranial hemorrhage. Laboratory hallmark is prolonged prothrombin time with normal aPTT. Recombinant activated FVII (rFVIIa) and plasma‐derived concentrates are effective for on‐demand and prophylactic therapy, with liver transplantation providing definitive correction in severe cases.

Conclusion & Clinical Utility

Definitive gene–disease validity, robust genetic and functional concordance, and available targeted therapies establish F7 testing as critical for diagnosis, family screening, and personalized management of congenital factor VII deficiency. Key take‐home: biallelic pathogenic F7 variants reliably predict bleeding risk and guide effective replacement strategies.

References

• Thrombosis and haemostasis • 1994 • Factor VII Mie: homozygous asymptomatic type I deficiency caused by an amino acid substitution of His(CAC) for Arg(247)(CGC) in the catalytic domain. PMID:7974346
• Thrombosis and haemostasis • 2018 • Activation of Endoplasmic Reticulum Stress and Unfolded Protein Response in Congenital Factor VII Deficiency. PMID:29618153
• Blood coagulation & fibrinolysis • 2017 • F7 gene variants modulate protein levels in a large cohort of patients with factor VII deficiency. Results from a genotype-phenotype study. PMID:28447100
• Thrombosis and haemostasis • 2012 • Lethal factor VII deficiency due to novel mutations in the F7 promoter: functional analysis reveals disruption of HNF4 binding site. PMID:22628013

Evidence Based Scoring (AI generated)