Abstract
Diagnosis of rare bleeding disorders is challenging and there are several differential diagnostics issues. Next-generation sequencing (NGS) is a useful tool to overcome these problems. The aim of this study was to demonstrate the usefulness of molecular genetic investigations by summarizing the diagnostic work on cases with certain bleeding disorders. Here we report only those, in whom NGS was indicated due to uncertainty of diagnosis or if genetic confirmation of initial diagnosis was required. Based on clinical and/or laboratory suspicion of von Willebrand disease (vWD, n = 63), hypo-or dysfibrinogenemia (n = 27), hereditary hemorrhagic telangiectasia (HHT, n = 10) and unexplained activated partial thromboplastin time (APTT) prolongation (n = 1), NGS using Illumina platform was performed. Gene panel covered 14 genes (ACVRL1, ENG, MADH4, GDF2, RASA1, F5, F8, FGA, FGB, FGG, KLKB1, ADAMTS13, GP1BA and VWF) selected on the basis of laboratory results. We identified forty-seven mutations, n = 29 (6 novel) in vWD, n = 4 mutations leading to hemophilia A, n = 10 (2 novel) in fibrinogen disorders, n = 2 novel mutations in HHT phenotype and two mutations (1 novel) leading to prekallikrein deficiency. By reporting well-characterized cases using standardized, advanced laboratory methods we add new pieces of data to the continuously developing “bleeding disorders databases”, which are excellent supports for clinical patient management.
Highlights
Correct and detailed laboratory diagnosis of bleeding disorders is of key importance in order to offer the adequate therapeutic strategy to patients
Screening tests of coagulation were performed on a Siemens BCS-XP coagulometer (Siemens, Marburg, Germany); Innovin and Pathromtin SL were used for prothrombin time (PT) and activated partial thromboplastin time (APTT) determination, respectively (Siemens), and Labexpert Thrombin time and fibrinogen reagents were used for thrombin time (TT) and Clauss-fibrinogen determination, respectively (Labexpert, Debrecen, Hungary)
Four patients were re-classified to hemophilia A based on the Next-generation sequencing (NGS) results
Summary
Correct and detailed laboratory diagnosis of bleeding disorders is of key importance in order to offer the adequate therapeutic strategy to patients. Certain subtypes of vWD (see below) have a sufficiently low frequency to be considered as rare [2,3]. Due to the low prevalence of congenital bleeding disorders the availability of experienced diagnostic laboratories is scarce. Diagnosis of rare bleeding disorders is challenging and there are several differential diagnostic issues. In coagulation disorders laboratory screening tests are prothrombin time (PT), activated partial thromboplastin time (APTT) and thrombin time (TT) [4]. These clotting time assays are easy to perform and are widely available at a relatively low cost
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