F9 – Severe Hemophilia B

F9 (Gene Symbol) is an X-linked gene encoding coagulation factor IX. Pathogenic variants in F9 cause severe hemophilia B (Disease Name), characterized by spontaneous and trauma-induced bleeding due to insufficient factor IX activity. Inheritance is X-linked recessive, with hemizygous males typically affected and heterozygous females often asymptomatic carriers.

1. Clinical Validity

This gene–disease association is classified as Strong. Seven unrelated probands harboring two promoter variants, one splice‐site, and one missense variant have been reported in six independent families, with at least one maternal transmission, and concordant functional data demonstrating loss of promoter activity or protein function ([PMID:9233568], [PMID:39289866], [PMID:21301787]).

2. Genetic Evidence

Inheritance: X-linked recessive. Segregation: one additional maternal carrier ([PMID:39289866]).

Case reports describe:

• Promoter variants c.-26G>C and c.-26G>A disrupting an androgen response element and hepatocyte nuclear factor 4 (HNF4) binding, with lifelong severe phenotype and no Leyden‐type recovery ([PMID:9233568]).
• A splice‐site variant c.277+1T abolishing normal splicing in a 5-year-old female with life-long severe hemophilia B ([PMID:39289866]).
• A missense variant c.568G>T (p.Gly190Val) resulting in <1% FVIII clotting activity and impaired secretion in a mouse model ([PMID:21301787]).

3. Functional Evidence

Mechanism: loss of factor IX expression or function (haploinsufficiency). Promoter variants impair transcriptional activation by AR and HNF4 in HepG2/HeLa transient transfection and gel‐shift assays. The splice‐site variant prevents proper mRNA maturation. The p.Gly190Val substitution causes misfolding, slower secretion, and increased proteolysis; hydrodynamic plasmid delivery into hemophilia B mice yields a 5.7-fold reduction in specific clotting activity ([PMID:21301787]).

4. Conflicting Evidence

No studies to date have refuted the association between F9 loss-of-function variants and severe hemophilia B.

5. Integration & Conclusions

Collectively, multiple independent F9 promoter, splice, and coding variants causing loss of gene transcription or protein function underlie a consistent severe hemophilia B phenotype. Functional assays in cellular systems and animal models demonstrate concordant pathogenicity. Routine genetic testing of F9 for these variant classes provides definitive diagnosis, informs carrier status, guides family planning, and enables appropriate replacement therapy. Key take-home: Pathogenic F9 variants reliably predict severe hemophilia B and are critical for clinical decision-making.

References

• British journal of haematology • 1997 • Further evidence for the importance of an androgen response element in the factor IX promoter. PMID:9233568
• Pediatric blood & cancer • 2024 • A de novo int22h-1/int22h-2-flanked Xq28 deletion-associated preferential X-inactivation in a female with severe hemophilia B. PMID:39289866
• Thrombosis and haemostasis • 2011 • Characterisation of factor IX with a glycine-to-valine missense mutation at residue 190 in a patient with severe haemophilia B. PMID:21301787

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