The relationship between FGB and congenital fibrinogen deficiency inherited in the autosomal recessive and dominant patterns has been evaluated using the ClinGen Clinical Validity Framework as of January, 2020. This association was made using case-level and experimental data. More than a 30 pathogenic variants in this gene are reported in humans, ranging from partial deletions and duplications, nonsense, frameshift, missense and splicing variants. Congenital fibrinogen deficiency is characterized by quantitative and qualitative defects in fibrinogen. It may manifest as afibrinogenemia, dysfibrinogenemia and hypodysfibrinogenemia. Clinical symptoms include a bleeding diathesis and/or a thrombotic phenotype.
Summary of Case Level Data (12 points): The association is seen in at least 10 probands in 8 publications (PMID: 23266225, 25629419, 24560896, 15070683, 12893758, 12161363, 23560673, 12511408). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached.
The mechanism for disease have been reported to be heterozygous as well as biallelic loss of function (PMID: 23266225, PMID:15070683).
Summary of Experimental Data (3 points): FGB encodes the β subunit of the coagulation factor, fibrinogen, which is a hexamer of three subunit chains (PMID: 22836683). The Bβ fibrinopeptide along with Aα fibrinopeptide interact with thrombin, which catalyzes the conversion of fibrinogen to fibrin (PMID: 15572239). It is synthesized in the liver and secreted into the plasma (PMID: 20921339). A zebrafish model that recapitulate fibrinogen deficiency is reported (PMID: 24098662).
In summary, the FGB-Congenital fibrinogen deficiency gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hemostasis/Thrombosis GCEP on January 22, 2020. (SOP Version 7)
Lumping & Splitting information: OMIM assertions - (1) Congenital Afibrinogenemia (MIM: 202400); (2) Congenital Dysfibrinogenemia (MIM: 616004); (3) Congenital Hypofibrinogenemia (MIM: 202400). Orphanet assertions - (1) Familial afibrinogenemia; (2) Familial dysfibrinogenemia; (3) Familial hypodysfibrinogenemia; (4) Familial hypofibrinogenemia. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) underlying the disease entities: Congenital Afibrinogenemia, Congenital Dysfibrinogenemia, Congenital Hypodysfibrinogenemia and Congenital Hypofibrinogenemia. These entities have been lumped together under Congenital Fibrinogen Deficiency.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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