F13A1 – Congenital Factor XIII Deficiency

Congenital factor XIII deficiency is an autosomal recessive bleeding disorder caused predominantly by pathogenic variants in the F13A1 gene, encoding the A subunit of coagulation factor XIII (Gene Symbol). A homozygous missense mutation Leu667Pro was identified in three affected siblings from a consanguineous Canadian family, with heterozygous parents and additional carriers detected by MspI digestion of exon 14 (PMID:8547093).

Large case series further substantiate this association. In an Indian cohort of 37 unrelated patients, direct sequencing revealed 25 distinct F13A1 variants (10 missense, 9 nonsense, 3 splice site, 3 deletions), including 14 novel mutations, confirming high allelic heterogeneity in severe deficiency (PMID:26852661). Similarly, analysis of 73 international patients treated with recombinant FXIII-A2 identified 51 unique mutations, encompassing missense, frameshift, splice, and deep intronic changes (PMID:28520207).

The variant spectrum includes frequent missense substitutions (e.g., Arg682His, c.2045G>A (p.Arg682His)) and recurrent splice-site defects, such as the IVS5-1G>A founder allele in European families (PMID:17549292). Loss-of-function alleles (nonsense, frameshift) and in-frame duplications also contribute to severe phenotypes, while hypomorphic splice mutations permit residual A-subunit expression and milder clinical courses (PMID:9028951).

Functional studies demonstrate that missense mutants often impair protein folding, dimerization, and stability. Expression of Arg261His and Val415Phe in yeast reduced transglutaminase activity and enzyme levels (PMID:10027709), while Y283C showed defective dimer formation and heterotetramer assembly in mammalian cells (PMID:11695887). Splice-site assays of intron C mutations confirmed aberrant transcript profiles with partial correct splicing correlating with residual activity (PMID:9028951).

No studies refute the F13A1–congenital factor XIII deficiency link; all large registries and molecular analyses consistently support pathogenicity of F13A1 variants in this disorder.

Collectively, F13A1 deficiency meets ClinGen criteria for a definitive gene–disease relationship, with robust genetic and experimental evidence. Early molecular diagnosis enables carrier detection, prenatal testing, and tailored replacement therapy, reducing life-threatening hemorrhages.

Key Take-home: F13A1 testing is critical for definitive diagnosis and family planning in congenital factor XIII deficiency.

References

• British Journal of Haematology • 1995 • Factor XIIIA Calgary: a candidate missense mutation (Leu667Pro) in the beta barrel 2 domain of the factor XIIIA subunit. PMID:8547093
• Blood Cells, Molecules & Diseases • 2016 • Genetic basis of severe factor XIII deficiency in a large cohort of Indian patients: Identification of fourteen novel mutations. PMID:26852661
• Haemophilia • 2017 • Comparison of F13A1 gene mutations in 73 patients treated with recombinant FXIII-A2. PMID:28520207
• Blood • 1997 • Molecular mechanism of a mild phenotype in coagulation factor XIII (FXIII) deficiency: a splicing mutation permitting partial correct splicing of FXIII A-subunit mRNA. PMID:9028951
• British Journal of Haematology • 1999 • Identification and characterization of two missense mutations causing factor XIIIA deficiency. PMID:10027709
• 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

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