Compound Heterozygous Mutations in FGA Cause Congenital Afibrinogenemia: A Case Report and Literature Review.

BACKGROUND

Congenital afibrinogenemia is an extremely rare autosomal recessive bleeding disorder with an estimated incidence of one in one million, caused by mutations in the fibrinogen-encoding genes.

METHODS

We report a genetically confirmed case of FGA-related congenital afibrinogenemia in a 9-year-old female child. Comprehensive coagulation analysis revealed undetectable fibrinogen activity (FIB:C, < 0.2 g/L) as measured by the Clauss assay, along with significantly prolonged prothrombin time, activated partial thromboplastin time, and thrombin time.

RESULTS

Next-generation sequencing targeting coagulation-related genes identified compound heterozygous mutations in FGA (NM_000508): a paternal nonsense mutation c.502C>T (p.Arg168Ter) in Exon 4 and a maternal frameshift mutation c.668delT (p.Leu223ArgfsX2) in Exon 5. These pathogenic variants were further confirmed by Sanger sequencing in the proband and her parents, which demonstrated that the proband carried the two FGA variants in a compound heterozygous state, with paternal inheritance of c.502C>T and maternal inheritance of c.668delT.

CONCLUSION

This case expands the genotype-phenotype correlation database for fibrinogen disorders and underscores the necessity of molecular diagnosis for congenital coagulation defects.