F7 – factor VII deficiency

Autosomal recessive F7 variants underlie congenital factor VII deficiency, a rare bleeding disorder characterized by prolonged prothrombin time and variable hemorrhagic manifestations. Over 100 unrelated probands with biallelic F7 mutations have been reported across diverse populations, with segregation in multiple families and concordant functional defects in vitro ([PMID:10862079]; [PMID:11129332]).

Inheritance is autosomal recessive, with affected individuals harboring two pathogenic alleles and heterozygotes often asymptomatic. Segregation analysis across at least eight families supports pathogenicity, including consanguineous pedigrees exhibiting classic coagulation defects (segregation in 8 families).

The variant spectrum includes missense (e.g., c.1190C>T (p.Thr397Met)), splice‐site (c.364+1G>C), promoter (–61T>G), frameshift (c.581del (p.Gly194fs)), and deep‐intronic alleles. Founder mutations such as A244V in Iranian and Moroccan Jewish populations further demonstrate recurrent pathogenic alleles ([PMID:17287630]).

Functional assays consistently reveal haploinsufficiency via defective protein secretion, impaired tissue factor binding, and aberrant splicing. CHO cell expression of FVII359M shows intracellular retention and Endo H sensitivity ([PMID:8652821]); minigene splicing studies confirm exon skipping due to IVS5–1G>A ([PMID:19601987]).

Clinical heterogeneity is evidenced by asymptomatic homozygotes and symptomatic individuals with similar FVII levels, indicating that modifier polymorphisms and environmental triggers modulate bleeding risk ([PMID:8978290]).

Integration of genetic and experimental data establishes a definitive gene–disease link. Genetic testing of F7 informs diagnosis, family counseling, and periprocedural management. Key Take-home: Biallelic F7 mutations cause autosomal recessive factor VII deficiency with robust genotype–phenotype correlations supported by extensive functional validation.

References

• Blood • 1996 • A Thr359Met mutation in factor VII of a patient with a hereditary deficiency causes defective secretion of the molecule. PMID:8652821
• Blood • 1997 • Severe factor VII deficiency due to a mutation disrupting a hepatocyte nuclear factor 4 binding site in the factor VII promoter. PMID:8978290
• Human genetics • 2000 • Molecular analysis of the genotype-phenotype relationship in factor VII deficiency. PMID:11129332
• Human mutation • 2000 • Twenty two novel mutations of the factor VII gene in factor VII deficiency. PMID:10862079
• Haemophilia • 2009 • Using a minigene approach to characterize a novel splice site mutation in human F7 gene causing inherited factor VII deficiency in a Chinese pedigree. PMID:19601987

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