{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T23:24:06Z","timestamp":1787095446563,"version":"build-2736575974"},"reference-count":34,"publisher":"Georg Thieme Verlag KG","issue":"06","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Semin Thromb Hemost"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Congenital fibrinogen disorders (CFDs) result from deficiencies in the fibrinogen-encoding genes FGA, FGB, and FGG, causing either quantitative or qualitative fibrinogen abnormalities. In this study, we conducted an extensive evaluation on clinical, laboratory, and genetic characteristics of 102 CFD patients. Fibrinogen levels were determined by Clauss method and\/or prothrombin time (PT)-derived method. Routine coagulation parameters including PT, activated partial thromboplastin time (APTT), and thrombin time (TT) were also assessed. Genetic mutations were detected through either next-generation sequencing or comprehensive whole-exome sequencing. The case series comprised 38 males and 64 females, with a median diagnosis age of 33 years. In patients where laboratory results were available, the function fibrinogen levels tested by Clauss method were decreased, whereas only 51.7% exhibited reduced fibrinogen concentrations by PT-derived method. A total of 55 germline mutations were identified, including 26 novel mutations not previously documented in the literature. Forty-two percent of unrelated patients were carriers of hotspot mutations. The laboratory results and clinical symptoms were highly variable among patients, even within patients harboring the same mutation. However, TT was significantly prolonged in qualitative CFDs compared with quantitative CFDs. All the patients harboring the hotspot mutations showed qualitative deficiency of fibrinogen. We also demonstrated that qualitative CFDs were particularly prone to harboring missense variants, whereas nearly all the null mutations were classified into the quantitative group. This study presents a genetic landscape of CFD patients, and their gene\u2013phenotype relationships. The novel identified genetic variants expand the known genetic spectrum of CFDs.<\/jats:p>","DOI":"10.1055\/a-2731-2301","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:16:23Z","timestamp":1764202583000},"page":"732-740","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Characterization of Congenital Fibrinogen Disorders: A Retrospective Analysis of 102 Unrelated Patients in China"],"prefix":"10.1055","volume":"52","author":[{"given":"Jiaoyuan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjun","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dengju","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"issue":"08","key":"ref1","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1055\/s-0042-1756187","article-title":"One hundred years of congenital fibrinogen disorders","volume":"48","author":"A Casini","year":"2022","journal-title":"Semin Thromb Hemost"},{"issue":"02","key":"ref2","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1055\/s-0044-1788898","article-title":"Clinical, laboratory, and molecular aspects of congenital fibrinogen disorders","volume":"51","author":"A Casini","year":"2025","journal-title":"Semin Thromb Hemost"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"109134","DOI":"10.1016\/j.thromres.2024.109134","article-title":"Regulation of fibrinogen synthesis","volume":"242","author":"D A Dobson","year":"2024","journal-title":"Thromb Res"},{"issue":"11","key":"ref4","doi-asserted-by":"crossref","first-page":"3005","DOI":"10.1016\/j.jtha.2023.08.014","article-title":"Fibrinogen and fibrin: synthesis, structure, and function in health and disease","volume":"21","author":"A S Wolberg","year":"2023","journal-title":"J Thromb Haemost"},{"issue":"06","key":"ref5","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1182\/bloodadvances.2023012186","article-title":"Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the prospective rare bleeding disorders database","volume":"8","author":"S Mohsenian","year":"2024","journal-title":"Blood Adv"},{"issue":"09","key":"ref6","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1111\/jth.14216","article-title":"Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH","volume":"16","author":"A Casini","year":"2018","journal-title":"J Thromb Haemost"},{"issue":"12","key":"ref7","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1002\/ajh.21293","article-title":"Laboratory testing for fibrinogen abnormalities","volume":"83","author":"M Verhovsek","year":"2008","journal-title":"Am J Hematol"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: improving access to variant interpretations and supporting evidence","volume":"46","author":"M J Landrum","year":"2018","journal-title":"Nucleic Acids Res"},{"issue":"04","key":"ref9","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1055\/s-0036-1571340","article-title":"Laboratory and genetic investigation of mutations accounting for congenital fibrinogen disorders","volume":"42","author":"M Neerman-Arbez","year":"2016","journal-title":"Semin Thromb Hemost"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.thromres.2022.07.005","article-title":"Congenital (hypo-)dysfibrinogenemia and bleeding: a systematic literature review","volume":"217","author":"Y Li","year":"2022","journal-title":"Thromb Res"},{"issue":"09","key":"ref11","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1111\/j.1538-7836.2010.03975.x","article-title":"ISTH\/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders","volume":"8","author":"F Rodeghiero","year":"2010","journal-title":"J Thromb Haemost"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.thromres.2020.07.023","article-title":"Fibrinogen Clauss and prothrombin time derived method ratio can differentiate dysfibrinogenemia from hypofibrinogenemia and hyperfibrinogenemia","volume":"194","author":"M Luo","year":"2020","journal-title":"Thromb Res"},{"issue":"04","key":"ref13","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","article-title":"REVEL: an ensemble method for predicting the pathogenicity of rare missense variants","volume":"99","author":"N M Ioannidis","year":"2016","journal-title":"Am J Hum Genet"},{"issue":"03","key":"ref14","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting splicing from primary sequence with deep learning","volume":"176","author":"K Jaganathan","year":"2019","journal-title":"Cell"},{"issue":"12","key":"ref15","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1016\/j.ajhg.2022.10.013","article-title":"Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3\/BP4 criteria","volume":"109","author":"V Pejaver","year":"2022","journal-title":"Am J Hum Genet"},{"issue":"05","key":"ref16","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"S Richards","year":"2015","journal-title":"Genet Med"},{"issue":"01","key":"ref17","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.ajhg.2023.11.009","article-title":"ClinGen guidance for use of the PP1\/BS4 co-segregation and PP4 phenotype specificity criteria for sequence variant pathogenicity classification","volume":"111","author":"L G Biesecker","year":"2024","journal-title":"Am J Hum Genet"},{"issue":"03","key":"ref18","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1182\/blood-2014-06-582866","article-title":"Natural history of patients with congenital dysfibrinogenemia","volume":"125","author":"A Casini","year":"2015","journal-title":"Blood"},{"issue":"04","key":"ref19","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1093\/labmed\/lmx050","article-title":"Coagulation testing in the core laboratory","volume":"48","author":"W E Winter","year":"2017","journal-title":"Lab Med"},{"issue":"11","key":"ref20","first-page":"1761","article-title":"Fibrinogen determination according to Clauss: commutability assessment of International and commercial standards and quality control samples","volume":"55","author":"A MHP van den Besselaar","year":"2017","journal-title":"Clin Chem Lab Med"},{"issue":"01","key":"ref21","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1111\/ijlh.14201","article-title":"International Council for Standardisation in Haematology recommendations on fibrinogen assays, thrombin clotting time and related tests in the investigation of bleeding disorders","volume":"46","author":"I Mackie","year":"2024","journal-title":"Int J Lab Hematol"},{"issue":"04","key":"ref22","doi-asserted-by":"crossref","first-page":"e22322","DOI":"10.1002\/jcla.22322","article-title":"Combined use of Clauss and prothrombin time-derived methods for determining fibrinogen concentrations: screening for congenital dysfibrinogenemia","volume":"32","author":"L Xiang","year":"2018","journal-title":"J Clin Lab Anal"},{"issue":"06","key":"ref23","doi-asserted-by":"crossref","first-page":"e428","DOI":"10.1016\/j.thromres.2010.09.004","article-title":"Comparison of the fibrinogen Clauss assay and the fibrinogen PT derived method in patients with dysfibrinogenemia","volume":"126","author":"W Miesbach","year":"2010","journal-title":"Thromb Res"},{"issue":"06","key":"ref24","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/0049-3848(94)90287-9","article-title":"Screening of dysfibrinogenaemia using the fibrinogen function versus antigen concentration ratio","volume":"76","author":"B Krammer","year":"1994","journal-title":"Thromb Res"},{"issue":"01","key":"ref25","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1111\/j.1365-2141.2007.06630.x","article-title":"Incorporation of fibrin molecules containing fibrinopeptide A alters clot ultrastructure and decreases permeability","volume":"138","author":"V H Flood","year":"2007","journal-title":"Br J Haematol"},{"issue":"03","key":"ref26","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1111\/bjh.19039","article-title":"Congenital fibrinogen disorders: strengthening genotype-phenotype correlations through novel genetic diagnostic tools","volume":"203","author":"R Ramanan","year":"2023","journal-title":"Br J Haematol"},{"issue":"03","key":"ref27","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1111\/hae.70026","article-title":"Pathogenic mechanisms in congenital afibrinogenemia: a systematic review of genetic variants","volume":"31","author":"Y Li","year":"2025","journal-title":"Haemophilia"},{"issue":"10","key":"ref28","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1055\/a-2514-7520","article-title":"Clinical and genetic characterization of 51 patients with congenital fibrinogen disorders from China","volume":"125","author":"Y Cai","year":"2025","journal-title":"Thromb Haemost"},{"issue":"04","key":"ref29","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1007\/s11239-020-02283-5","article-title":"Mutations in inherited fibrinogen disorders correlated with clinical features in the Chinese population","volume":"51","author":"Y Wan","year":"2021","journal-title":"J Thromb Thrombolysis"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.thromres.2019.08.012","article-title":"Genetic and clinical characterization of congenital fibrinogen disorders in Polish patients: identification of three novel fibrinogen gamma chain mutations","volume":"182","author":"E Wypasek","year":"2019","journal-title":"Thromb Res"},{"issue":"06","key":"ref31","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1111\/hae.14399","article-title":"Clinical features and genetic defect in six index patients with congenital fibrinogen disorders: three novel mutations with one common mutation in Taiwan's population","volume":"27","author":"M C Shen","year":"2021","journal-title":"Haemophilia"},{"issue":"11","key":"ref32","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1055\/s-0038-1673685","article-title":"Mutational epidemiology of congenital fibrinogen disorders","volume":"118","author":"A Casini","year":"2018","journal-title":"Thromb Haemost"},{"issue":"07","key":"ref33","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1182\/blood.V92.7.2195","article-title":"Gamma-chain dysfibrinogenemias: molecular structure-function relationships of naturally occurring mutations in the gamma chain of human fibrinogen","volume":"92","author":"H C C\u00f4t\u00e9","year":"1998","journal-title":"Blood"},{"issue":"06","key":"ref34","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1111\/jth.12916","article-title":"Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management","volume":"13","author":"A Casini","year":"2015","journal-title":"J Thromb Haemost"}],"container-title":["Seminars in Thrombosis and Hemostasis"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-2731-2301.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T22:32:47Z","timestamp":1787092367000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-2731-2301"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,26]]},"references-count":34,"journal-issue":{"issue":"06","published-online":{"date-parts":[[2026,8,18]]},"published-print":{"date-parts":[[2026,9]]}},"URL":"https:\/\/doi.org\/10.1055\/a-2731-2301","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0094-6176","1098-9064"],"issn-type":[{"value":"0094-6176","type":"print"},{"value":"1098-9064","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,26]]}}}