F13B – Congenital Factor XIII Deficiency

Congenital factor XIII deficiency is an autosomal recessive bleeding disorder characterized by delayed umbilical cord bleeding, subcutaneous and intramuscular hemorrhages, and a high risk of intracranial hemorrhage. While most cases are caused by biallelic F13A1 variants, pathogenic variants in F13B (HGNC:3534) disrupt the protective carrier subunit of the FXIII heterotetramer, leading to increased A‐subunit clearance and variable bleeding severity (PMID:16513532).

Genetic evidence for F13B involvement is limited to isolated case reports of homozygous or compound heterozygous variants. Two unrelated probands have been described: one with a splice junction and missense combination in F13B in the United States (PMID:16513532) and one Japanese patient homozygous for a founder missense variant (PMID:23407795). Parental carrier segregation was confirmed in the US family, and heterozygous relatives were asymptomatic without FXIII deficiency.

The variant spectrum in F13B deficiency is dominated by missense mutations affecting sushi domains and disulfide bonds. A recurrent variant, c.344G>A (p.Arg115His), has been reported in both bleeding and modifier contexts (PMID:16241947). No frameshift or large‐scale loss‐of‐function variants in F13B have been conclusively linked to deficiency.

Functional studies demonstrate that F13B missense variants impair subunit stability, assembly, and secretion. His95Arg increases A–B dissociation in plasma (PMID:16241947), Cys316Phe and Pro428Ser disrupt disulfide bonds and prevent proper tetramer formation (PMID:20331752), and systematic ablation of any of the 20 structural disulfides reduces secretion and stability in HEK293T cells (PMID:31013569). These models concordantly recapitulate the mild bleeding phenotype seen in patients.

No significant conflicting evidence has been reported; common polymorphisms in F13B have not been linked to severe hemorrhage. However, F13B variants may modify the phenotype of other coagulation disorders without causing overt FXIII deficiency.

In summary, biallelic F13B variants cause a clinically milder form of congenital FXIII deficiency via defective subunit stability and heterotetramer assembly. Functional assays robustly support pathogenicity, but the small number of unrelated probands limits the genetic evidence. Genetic testing for F13B should be considered in AR FXIII deficiency when F13A1 mutations are absent. The identification of F13B variants informs diagnosis, guides prophylactic replacement therapy, and may impact risk stratification in combined coagulopathies.

References

• Indian journal of pediatrics • 1993 • Hereditary factor XIII deficiency. PMID:8253495
• International journal of hematology • 2006 • Identification of a novel mutation combination in factor XIII deficiency: genetic update to the first reported case in the United States. PMID:16513532
• Thrombosis and haemostasis • 2007 • International registry on factor XIII deficiency: a basis formed mostly on European data. PMID:17549292
• Journal of thrombosis and haemostasis : JTH • 2005 • A novel polymorphism in the factor XIII B-subunit (His95Arg): relationship to subunit dissociation and venous thrombosis. PMID:16241947
• Biochemistry • 2001 • Impaired protein folding, dimer formation, and heterotetramer assembly cause intra- and extracellular instability of a Y283C mutant of the A subunit for coagulation factor XIII. PMID:11695887
• Haemophilia : the official journal of the World Federation of Hemophilia • 2010 • Mutations affecting disulphide bonds contribute to a fairly common prevalence of F13B gene defects: results of a genetic study in 14 families with factor XIII B deficiency. PMID:20331752
• International journal of molecular sciences • 2019 • Disruption of Structural Disulfides of Coagulation FXIII-B Subunit; Functional Implications for a Rare Bleeding Disorder. PMID:31013569

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