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DOI: 10.1055/s-0038-1673685
Mutational Epidemiology of Congenital Fibrinogen Disorders
Funding This project was supported by the Swiss National Science Foundation (grants #31003A-152633/I and #31003A_172864) and an unrestricted grant from the ISTH2007 Presidential Fund.Publikationsverlauf
12. Mai 2018
02. September 2018
Publikationsdatum:
17. Oktober 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201811/lookinside/thumbnails/10-1055-s-0038-1673685_180350-1.jpg)
Abstract
Background Numerous mutations in FGA, FGB or FGG lead to congenital fibrinogen disorders (CFDs), but their epidemiology is not well characterized. The aim of this study was to evaluate the molecular epidemiology of CFD and to develop a genotyping strategy.
Methods Genetic data from 266 unrelated CFD patients genotyped at our laboratory and from a CFD open access database (n = 1,142) were evaluated. We developed a step-wise screening strategy for the molecular diagnosis of CFD and prospectively tested this strategy on 32 consecutive CFD probands.
Results We identified 345 mutated alleles overall, among 187 heterozygous, 63 homozygous and 16 compound heterozygous individuals. Afibrinogenemia was almost always caused by null mutations (98.6%), mainly in FGA (85%). Hypofibrinogenemia was mainly caused by missense mutations of FGB or FGG (54.2%). Dysfibrinogenemia was almost always caused by heterozygous missense mutations (99.3%) in FGA and FGG. Hotspot mutations were prevalent among quantitative (33.1%) and qualitative fibrinogen disorders (71.1%). The mutational cluster at our laboratory was similar with that reported in the CFD open access database. The proposed step-wise genetic screening strategy proved efficient in both the development and validation samples for CFD: the screening of FGA exons 2, 4, 5 and FGG exon 8 and search for the 11 kb deletion of FGA led to the identification of approximately 80% of mutated alleles, including 15 new mutations.
Conclusion The described molecular epidemiology of CFD is complex. The proposed step-wise genetic screening strategy may provide an efficient way to identify causative mutations analysing a minimal number of exons.
Keywords
afibrinogenemia - congenital - hypofibrinogenemia - dysfibrinogenemia - hypodysfibrinogenaemia - mutationAuthors' Contributions
A. Casini, P. de Moerloose and M. Neerman-Arbez designed the research and wrote the article; A. Casini and M. Blondon extracted and analysed the data; A. Casini and M. Neerman-Arbez performed genetic analyses; M. Hanss provided data from the Human Fibrinogen Database; and V. Tintillier, M. Goodyer, A. Meral and M. Evim provided genetic samples and patients information (more than two patients in the prospective part of the study). All authors provided critical revisions to the manuscript.
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References
- 1 Casini A, de Moerloose P, Neerman-Arbez M. Clinical features and management of congenital fibrinogen deficiencies. Semin Thromb Hemost 2016; 42 (04) 366-374
- 2 Neerman-Arbez M, de Moerloose P, Casini A. Laboratory and genetic investigation of mutations accounting for congenital fibrinogen disorders. Semin Thromb Hemost 2016; 42 (04) 356-365
- 3 Palla R, Peyvandi F, Shapiro AD. Rare bleeding disorders: diagnosis and treatment. Blood 2015; 125 (13) 2052-2061
- 4 Asselta R, Duga S, Tenchini ML. The molecular basis of quantitative fibrinogen disorders. J Thromb Haemost 2006; 4 (10) 2115-2129
- 5 Hanss M, Biot F. A database for human fibrinogen variants. Ann N Y Acad Sci 2001; 936: 89-90
- 6 Vu D, Neerman-Arbez M. Molecular mechanisms accounting for fibrinogen deficiency: from large deletions to intracellular retention of misfolded proteins. J Thromb Haemost 2007; 5 (Suppl. 01) 125-131
- 7 Casini A, Neerman-Arbez M, Ariëns RA, de Moerloose P. Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management. J Thromb Haemost 2015; 13 (06) 909-919
- 8 Paraboschi EM, Duga S, Asselta R. Fibrinogen as a pleiotropic protein causing human diseases: the mutational burden of Aα, Bβ, and γ chains. Int J Mol Sci 2017; 18 (12) 2711-2726
- 9 Neerman-Arbez M, de Moerloose P, Bridel C. , et al. Mutations in the fibrinogen aalpha gene account for the majority of cases of congenital afibrinogenemia. Blood 2000; 96 (01) 149-152
- 10 Vu D, Bolton-Maggs PH, Parr JR, Morris MA, de Moerloose P, Neerman-Arbez M. Congenital afibrinogenemia: identification and expression of a missense mutation in FGB impairing fibrinogen secretion. Blood 2003; 102 (13) 4413-4415
- 11 Casini A, Lukowski S, Quintard VL. , et al. FGB mutations leading to congenital quantitative fibrinogen deficiencies: an update and report of four novel mutations. Thromb Res 2014; 133 (05) 868-874
- 12 Brennan SO, Maghzal G, Shneider BL, Gordon R, Magid MS, George PM. Novel fibrinogen gamma375 Arg-->Trp mutation (fibrinogen aguadilla) causes hepatic endoplasmic reticulum storage and hypofibrinogenemia. Hepatology 2002; 36 (03) 652-658
- 13 Dib N, Quelin F, Ternisien C. , et al. Fibrinogen angers with a new deletion (gamma GVYYQ 346-350) causes hypofibrinogenemia with hepatic storage. J Thromb Haemost 2007; 5 (10) 1999-2005
- 14 Galanakis DK, Neerman-Arbez M, Scheiner T. , et al. Homophenotypic Aalpha R16H fibrinogen (Kingsport): uniquely altered polymerization associated with slower fibrinopeptide A than fibrinopeptide B release. Blood Coagul Fibrinolysis 2007; 18 (08) 731-737
- 15 Acharya SS, Dimichele DM. Rare inherited disorders of fibrinogen. Haemophilia 2008; 14 (06) 1151-1158
- 16 Neerman-Arbez M, de Moerloose P, Honsberger A. , et al. Molecular analysis of the fibrinogen gene cluster in 16 patients with congenital afibrinogenemia: novel truncating mutations in the FGA and FGG genes. Hum Genet 2001; 108 (03) 237-240
- 17 Asselta R, Platè M, Robusto M. , et al. Clinical and molecular characterisation of 21 patients affected by quantitative fibrinogen deficiency. Thromb Haemost 2015; 113 (03) 567-576
- 18 Casini A, Blondon M, Lebreton A. , et al. Natural history of patients with congenital dysfibrinogenemia. Blood 2015; 125 (03) 553-561
- 19 Haverkate F, Samama M. Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC Subcommittee on Fibrinogen. Thromb Haemost 1995; 73 (01) 151-161
- 20 Sivapalaratnam S, Collins J, Gomez K. Diagnosis of inherited bleeding disorders in the genomic era. Br J Haematol 2017; 179 (03) 363-376
- 21 Fernández-Cadenas I, Penalba A, Boada C. , et al. Exome sequencing and clot lysis experiments demonstrate the R458C mutation of the alpha chain of fibrinogen to be associated with impaired fibrinolysis in a family with thrombophilia. J Atheroscler Thromb 2016; 23 (04) 431-440
- 22 Mukai S, Nagata K, Ikeda M. , et al. Genetic analyses of novel compound heterozygous hypodysfibrinogenemia, Tsukuba I: FGG c.1129+62_65 del AATA and FGG c.1299+4 del A. Thromb Res 2016; 148: 111-117