A novel missense variant (c.1172A>T, p.Asn391Ile) in the gamma chain of fibrinogen causing hypodysfibrinogenemia in an asymptomatic Danish family and review of adjacent variants

Congenital fibrinogen disorders are rare. We describe a novel fibrinogen γ-chain variant and review adjacent variants to contextualize its significance. A woman investigated for infertility and her mother underwent hemostatic evaluation including functional, antigenic fibrinogen, and fibrin turbidity assays. Whole-exome sequencing (WES) was performed. Both asymptomatic individuals had hypodysfibrinogenemia with disproportionately reduced functional and antigenic fibrinogen and impaired fibrin polymerization with prolonged lag phase and reduced maximal slope. WES revealed a novel heterozygous FGG missense variant, c.1172A>T (p.Asn391Ile; γ[365]Asn>Ile), in both individuals. According to ISTH-SSC guideline, both met subtype 4C (mild hypodysfibrinogenemia). Across 11 published cases with variants in γ361–369, six showed impaired fibrin polymerization and phenotypes ranged from bleeding ( n = 6) and venous thrombosis ( n = 2) to asymptomatic ( n = 2) and hepatic fibrinogen storage disease ( n = 1). FGG p.Asn391Ile variant is associated with hypodysfibrinogenemia and impaired fibrin polymerization, but current evidence is insufficient to define its clinical phenotype.