F10 – Factor X Deficiency

Factor X (encoded by F10 https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:3528) is a vitamin K–dependent serine protease essential for thrombin generation. Autosomal recessive variants in F10 cause congenital factor X deficiency (MONDO:0002247), a bleeding disorder with an incidence of ~1:1 000 000 ([PMID:19598069]). Patients present with easy bruising, hemarthroses, mucosal and intracranial hemorrhages.

Clinical Validity

Definitive: Extensive evidence from >100 probands ([PMID:19598069]), segregation in 12 affected relatives across multiple consanguineous pedigrees ([PMID:10746568]; [PMID:12028042]) and concordant functional data.

Genetic Evidence

Inherited in an autosomal recessive pattern, F10 deficiency has been reported in diverse populations. Molecular analysis of 14 unrelated patients identified 13 novel mutations and familial segregation ([PMID:10746568]). In 13 Iranian families, nine homozygous mutations correlated with type I/II deficiencies ([PMID:12028042]). Case series describe compound heterozygotes with a deletion of exon 6 and c.856G>A (p.Val286Met) ([PMID:19404516]). Variant spectrum includes missense, splice, small indel and deep intronic changes; recurrent founder alleles have been noted in Middle Eastern cohorts.

Functional Evidence

Mechanistic studies have characterized signal peptide and Gla domain mutants. The FX Vorarlberg p.Glu54Lys and p.Glu102Lys mutants impair Ca2+ binding and extrinsic activation ([PMID:1973167]). A mouse knockout of exon 8 is perinatal lethal, while the Friuli Pro343Ser model (5–9% activity) rescues lethality and demonstrates maternal transfer of FX ([PMID:18036190]). In vitro expression assays of p.Val286Met confirm severely reduced antigen and activity levels, consistent with null phenotypes ([PMID:19404516]).

Clinical Applications

Genetic testing enables prenatal diagnosis via direct mutation and linkage analysis ([PMID:12813758]). Plasma-derived FX concentrates or prothrombin complex concentrates are used prophylactically or peri-operatively; recombinant therapies and pdFX improve management of life-threatening bleeds.

Conclusion

Integrating robust genetic segregation, a broad variant spectrum, and concordant functional studies establishes a definitive F10–factor X deficiency association. Early molecular diagnosis guides clinical management and family counseling. Key take-home: F10 variant detection is critical for diagnosis, risk stratification, and tailored hemostatic therapy.

References

• Human genetics • 2000 • Molecular analysis of the genotype-phenotype relationship in factor X deficiency. PMID:10746568
• British journal of haematology • 2002 • Gene mutations and three-dimensional structural analysis in 13 families with severe factor X deficiency. PMID:12028042
• Seminars in thrombosis and hemostasis • 2009 • Factor X deficiency. PMID:19598069
• The Journal of biological chemistry • 1990 • Molecular defect (Gla+14----Lys) and its functional consequences in a hereditary factor X deficiency (factor X “Vorarlberg”). PMID:1973167
• Hamostaseologie • 2009 • Identification of a novel factor X deletion in combination with a missense mutation in the F10 gene - Genotype-phenotype correlation in a girl with severe factor X deficiency. PMID:19404516
• Journal of thrombosis and haemostasis : JTH • 2008 • A viable mouse model of factor X deficiency provides evidence for maternal transfer of factor X. PMID:18036190

Evidence Based Scoring (AI generated)