F2 – Congenital Prothrombin Deficiency

Congenital prothrombin deficiency (MONDO:0013361) is an autosomal recessive bleeding disorder caused by biallelic loss-of-function variants in F2 (HGNC:3535), which encodes prothrombin (factor II). Affected individuals present with severely reduced prothrombin activity and antigen, leading to mucocutaneous and deep‐tissue hemorrhages, and in some cases early-onset seizures due to intracranial bleeding (HP:0001892; HP:0002197).

Inheritance is autosomal recessive, with at least five unrelated probands reported carrying compound heterozygous or homozygous F2 variants ([PMID:9351523]; [PMID:9890721]; [PMID:33977210]; [PMID:38601422]; [PMID:19750864]). Variants include frameshift, stop‐gain, splice‐region, and missense alleles across exons 8–14.

The variant spectrum comprises a single‐nucleotide deletion c.7248_7249del (p.Ser249Ter) and a missense substitution c.1147C>T (p.Arg383Trp) in exon 10 ([PMID:9351523]), along with other stop‐gain (e.g., p.Trp569Ter), splice‐junction, and hypomorphic alleles identified in different populations.

Segregation studies in two families confirm cosegregation of F2 pathogenic alleles with hypoprothrombinemia in two additional affected relatives ([PMID:9890721]; [PMID:33977210]). These analyses support a recessive inheritance pattern and pathogenic impact on prothrombin levels.

Functional assays demonstrate loss-of-function as the disease mechanism. Frameshift variants cause premature termination, and modeling of the p.Arg383Trp substitution reveals disruption of a surface‐exposed exosite and reduced thrombin stability and fibrinogen clotting activity ([PMID:9351523]).

Taken together, the genetic and experimental data fulfill criteria for a Moderate clinical validity classification of F2 in congenital prothrombin deficiency. F2 molecular testing enables definitive diagnosis, guides bleeding risk assessment, and informs genetic counseling.

References

• Blood coagulation & fibrinolysis • 1997 • Molecular analysis of a compound heterozygote for hypoprothrombinemia and dysprothrombinemia (-G 7248/7249 and ARG 340 TRP). PMID:9351523
• Blood coagulation & fibrinolysis • 1998 • Two novel mutations in the prothrombin gene cause severe bleeding in a compound heterozygous patient. PMID:9890721
• Research and practice in thrombosis and haemostasis • 2021 • A case of congenital prothrombin deficiency with two concurrent mutations in the prothrombin gene. PMID:33977210
• Cureus • 2024 • Isolated Prothrombin Deficiency: A Case Report of a Rare Coagulation Disorder and Review of Literature. PMID:38601422
• JPMA. The Journal of the Pakistan Medical Association • 2009 • Hereditary prothrombin deficiency. PMID:19750864

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