Genetic Mutations Associated with Congenital Fibrinogen Disorders: Global Distribution and Clinical Outcomes

Authors: Nóbrega, T; Villaça, P; Okazaki, E; Rothschild, C; Stefanello, B; Rocha, T; Rocha, V; A Orsi, F

Affiliations: Hospital University of São Paulo, São Paulo, Brazil. Department of Pathology, School of Medical Sciences, University of Campinas, Campinas, Brazil. Hematology and Hemotherapy Center at UNICAMP, Campinas, Brazil.

Publication: Journal of thrombosis and thrombolysis;2025

ABSTRACT: Congenital fibrinogen disorders (CFD) are characterized by heterogeneous manifestations, from asymptomatic to severe bleeding or thrombosis, associated with genetic mutations in FGA, FGB, or FGG genes. As a result, diagnosis is challenging, particularly in low- and middle-income countries, where evidence is scarce. The aim of this review is to describe the distribution of CFD-associated genetic mutations across different regions of the world and their corresponding phenotypes. Data from MEDLINE and the French Group for the Study of Hemostasis and Thrombosis databases were qualitatively organized based on the United Nations regional classification. A total of 132 studies on CFD were selected from MEDLINE and GFHT fibrinogen database, comprising over 1000 mutations descriptions and approximately 340 unique mutations. FGA mutations are most associated with dys- or afibrinogenemia, while FGB mutations are associated with hypo- or afibrinogenemia and FGG with dys- or hypofibrinogenemia Across countries, the most common mutations in afibrinogenemia and hypofibrinogenemia were intronic variant sequence in FGA, p. Arg47stop in FGB, and mutations in exon 8 of FGG. Dysfibrinogenemia was associated with mutations in exon 2 of FGA, typically resulting in asymptomatic individuals and with mutations in exon 8 of FGG, which are associated with thrombosis. The majority of mutations related to CFD and their associated phenotypes have been reported in Western Europe, North America and East Asia. Evidence from Latin America, Southeast Asia, and Africa remains limited, with Brazil having only one study that evaluated CFD mutations. Data on CFD phenotypes and associated genetic mutations from low- and middle-income countries are necessary to ensure equity in the management of these rare diseases.