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Blueprint Genetics Bleeding Disorder/Coagulopathy Panel

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Bleeding Disorder/Coagulopathy Panel Test code: HE1301 Is a 71 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of an inherited bleeding disorder. Is not recommended for patients with a suspicion of severe Hemophilia A if the common inversions are not excluded by previous testing. An intron 22 inversion of the F8 gene is identified in 43%-45% individuals with severe hemophilia A and intron 1 inversion in 2%-5% (GeneReviews NBK1404; PMID:8275087, 8490618, 29296726, 27292088, 22282501, 11756167). This test does not detect reliably these inversions. About Bleeding Disorder/Coagulopathy Bleeding disorder refers to a heterogenous group of diseases caused by deficiencies in platelet function or coagulation factors. The bleeding disorders can be categorized into three groups: 1) the common inherited bleeding disorders, hemophilia A, B, and von Willebrand disease (VWD); (2) the rare inherited coagulation factor deficiencies; and (3) inherited platelet disorders (PMID: 24124085). VWD is the most common inherited bleeding disorder, affecting up to 1% of the general population and occuring with equal frequency among men and women. The phenotypes that are covered by the panel include VWD, hemophilia A and B, rare bleeding disorders, Hermansky Pudlak syndrome, Wiskott-Aldrich syndrome, Bernard Soulier syndrome, Glanzmann disease, thrombocytopenia 2, familial platelet syndrome with predisposition to acute myelogenous leukemia and gray platelet syndrome. The molecular knowledge gained from genetic testing is currently routinely used in the clinical care of the patients with hereditary bleeding disorder. Availability 4 weeks Gene Set Description Genes in the Bleeding Disorder/Coagulopathy Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD ABCG5 Sitosterolemia AR 13 42 ABCG8 Sitosterolemia AR 18 44 ACTN1 Bleeding disorder, platelet- AD 7 25 ADAMTS13 Schulman-Upshaw syndrome, Thrombotic thrombocytopenic purpura, AR 30 183 familial ANKRD26 Thrombocytopenia AD 6 21 AP3B1 Hermansky-Pudlak syndrome AR 14 34 ARPC1B Platelet abnormalities with eosinophilia and immune-mediated AR 2 4 inflammatory disease BLOC1S3 Hermansky-Pudlak syndrome AR 2 4 BLOC1S6 Hermansky-Pudlak syndrome AR 1 2 CYCS* Thrombocytopenia AD 2 3 https://blueprintgenetics.com/ DTNBP1 Hermansky-Pudlak syndrome AR 2 3 EFL1 Shwachman-Diamond syndrome 3 2 ETV6 Thrombocytopenia 5 AD 10 38 F10 Factor X deficiency AR 15 155 F11 Factor XI deficiency AD/AR 77 271 F12 Angioedema, Factor XII deficiency AD/AR 7 53 F13A1 Factor XIIIA deficiency AR 20 180 F2 Thrombophilia due to thrombin defect, Prothrombin deficiency, AD/AR 14 66 congenital F5 Factor V deficiency, Thrombophilia due to activated protein C AD/AR 19 157 resistance F7 Factor VII deficiency AR 27 322 F8* Hemophilia A XL 296 3205 F9 Hemophilia B, Warfarin sensitivity, Thrombophilia, due to factor IX XL 117 1281 defect FGA Afibrinogenemia, congenital, Dysfibrinogenemia, congenital, AD/AR 10 144 Hypodysfibrinogenemia, congenital, Familial visceral amyloidosis FGB Afibrinogenemia, congenital, Dysfibrinogenemia, congenital, AD/AR 6 92 Hypodysfibrinogenemia, congenital FGG Afibrinogenemia, congenital, Hypodysfibrinogenemia, AD/AR 7 127 Dysfibrinogenemia, congenital, Hypodysfibrinogenemia, congenital FLI1 Thrombocytopenia, Paris-Trousseau type, Bleeding disorder, platelet AD 7 7 type 21 FLNA Frontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, XL 133 257 Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defects FYB Thrombocytopenia 3 AR 2 2 GATA1 Anemia, without thrombocytopenia, Thrombocytopenia with beta- XL 21 15 thalessemia,, Dyserythropoietic anemia with thrombocytopenia GBA* Gaucher disease AR 84 488 GFI1B Bleeding disorder, platelet-type, 17 AD 6 9 GGCX Pseudoxanthoma elasticum-like disorder with multiple coagulation AD/AR/Digenic 13 42 factor deficiency, Vitamin K-dependent clotting factors, combined deficiency GP1BA Pseudo-von Willebrand disease, Bernard-Soulier syndrome AD/AR 9 73 GP1BB Giant platelet disorder, isolated, Bernard-Soulier syndrome AD/AR 5 53 GP9 Bernard-Soulier syndrome AR 6 42 https://blueprintgenetics.com/ HOXA11 Radioulnar synostosis with amegakaryocytic thrombocytopenia AD 1 1 HPS1* Hermansky-Pudlak syndrome AR 28 55 HPS3* Hermansky-Pudlak syndrome AR 10 17 HPS4 Hermansky-Pudlak syndrome AR 16 22 HPS5 Hermansky-Pudlak syndrome AR 20 31 HPS6 Hermansky-Pudlak syndrome AR 13 37 ITGA2 Fetal and neonatal alloimmune thrombocytopenia AD/AR 5 ITGA2B Glanzmann thrombasthenia AD/AR 22 234 ITGB3 Bleeding disorder, platelet-, Thrombocytopenia, neonatal alloimmune, AD/AR 18 165 Glanzmann thrombasthenia LMAN1 Combined factor V and VIII deficiency AR 5 37 MASTL Thrombocytopenia AD 5 MCFD2 Factor V & Factor VIII, combined deficiency of AR 8 20 MECOM Radioulnar synostosis with amegakaryocytic thrombocytopenia 2 AD 3 27 MPL Thrombocythemia, Amegakaryocytic thrombocytopenia AD/AR 23 55 MYH9 Sebastian syndrome, May-Hegglin anomaly, Epstein syndrome, AD 25 117 Fechtner syndrome, Macrothrombocytopenia and progressive sensorineural deafness, Deafness, autosomal dominant 17 NBEAL2 Gray platelet syndrome AR 10 51 P2RY12 Bleeding disorder, platelet- AD/AR 4 13 PRKACG Bleeding disorder, platelet-type, 19 AR 1 1 PROC Thrombophilia, hereditary AD/AR 36 387 PROS1* Thrombophilia, hereditary AD/AR 23 416 RASGRP2 Bleeding disorder, platelet-type, 18 AR 3 20 RBM8A*,# Thrombocytopenia - absent radius AD/AR 5 12 RUNX1 Platelet disorder, familial, with associated myeloid malignancy AD 47 101 SERPINC1 Antithrombin III deficiency AD/AR 44 412 SERPINF2 Alpha-2-plasmin inhibitor deficiency AD/AR 4 8 SLFN14 Thrombocytopenia AD/AR 4 4 SRC Thrombocytopenia, autosomal dominant, 6 AD 2 1 SRP54 Shwachman-Diamond syndrome AD 3 TBXA2R Bleeding disorder, platelet- AD 1 6 https://blueprintgenetics.com/ THBD Thrombophilia due to thrombomodulin defect, Hemolytic uremic AD 5 28 syndrome, atypical THPO Thrombocythemia 1 AD 5 10 TUBB1 Macrothrombocytopenia AD 2 7 VKORC1 Drug metabolism, VKORC1-related, Vitamin K-dependent clotting AD/AR 4 27 factors, combined deficiency VWF* Von Willebrand disease AD/AR 57 1009 WAS Neutropenia, severe congenital, Thrombocytopenia, Wiskott-Aldrich XL 57 439 syndrome WIPF1 Wiskott-Aldrich syndrome 2 AR 2 3 *Some regions of the gene are duplicated in the genome. Read more. # The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads), and/or the gene has exons listed under Test limitations section that are not included in the panel as they are not sufficiently covered with high quality sequence reads. The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#). Due to possible limitations these genes may not be available as single gene tests. Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), mitochondrial (mi), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Mitomap databases. Non-coding disease causing variants covered by the panel Gene Genomic HGVS RefSeq RS-number location HG19 ANKRD26 Chr10:27389371 c.-116C>G NM_014915.2 ANKRD26 Chr10:27389373 c.-118C>A NM_014915.2 ANKRD26 Chr10:27389374 c.-119C>A NM_014915.2 ANKRD26 Chr10:27389374 c.-119C>A/G NM_014915.2 ANKRD26 Chr10:27389376 c.-121A>C NM_014915.2 ANKRD26 Chr10:27389380 c.-127_-126delAT NM_014915.2 ANKRD26 Chr10:27389381 c.-126T>C NM_014915.2 ANKRD26 Chr10:27389381 c.-126T>G NM_014915.2 ANKRD26 Chr10:27389382 c.-127A>G NM_014915.2 ANKRD26 Chr10:27389382 c.-127A>T NM_014915.2 ANKRD26 Chr10:27389383 c.-128G>T NM_014915.2 https://blueprintgenetics.com/ ANKRD26 Chr10:27389383 c.-128G>A NM_014915.2 ANKRD26 Chr10:27389383 c.-128G>C NM_014915.2 ANKRD26 Chr10:27389389 c.-134G>A NM_014915.2 rs863223318 F11 Chr4:187186995 c.-456G>A NM_000128.3 F11 Chr4:187197061 c.595+11A>G NM_000128.3 rs534170853 F11 Chr4:187205426 c.1304+12G>A NM_000128.3 rs116667976 F12 Chr5:176836590 NM_000505.3 rs187018744 F13A1 Chr6:6320800 c.-19_-19+19delGGTAAGCCACCGACCCTGCA NM_000129.3 F2 Chr11:46742048 c.241-25C>G NM_000506.3 F2 Chr11:46761055 c.*97G>A NM_000506.4 rs1799963 F2 Chr11:46761064 c.*106T>A NM_000506.3 F2 Chr11:46761066 c.*108C>T NM_000506.3 rs562369397 F5 Chr1:169494158 c.5717-12T>A NM_000130.4 F5 Chr1:169521527 c.1296+268A>G NM_000130.4 F5 Chr1:169521984 c.1119-12C>G NM_000130.4 F7 Chr13:113760060 c.-96C>T NM_000131.4 F7 Chr13:113760062 c.-94C>G NM_000131.4 F7 Chr13:113760091 c.-65G>C NM_000131.4 F7 Chr13:113760094 NM_000131.4 F7 Chr13:113760094 c.-62C>T NM_000131.4 F7 Chr13:113760095 c.-61T>G NM_000131.4 F7 Chr13:113760096 NM_000131.4 F7 Chr13:113760096 NM_000131.4 F7 Chr13:113760097 c.-59T>G NM_000131.4 F7 Chr13:113760099 c.-57C>T NM_000131.4 F7 Chr13:113760101 NM_000131.4 F7 Chr13:113760101 NM_000131.4 F7 Chr13:113760112 c.-44T>C NM_000131.4 rs577393666 F7 Chr13:113760117 c.-39A>G NM_000131.4 F7 Chr13:113760124 c.-32A>C NM_000131.4 rs761212787 F7 Chr13:113760126 c.-30A>C NM_000131.4 rs539578931 https://blueprintgenetics.com/ F7 Chr13:113764993 c.131-11G>A NM_000131.4
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  • Haemostatic Problems in Liver Disease

    Haemostatic Problems in Liver Disease

    Gut: first published as 10.1136/gut.27.3.339 on 1 March 1986. Downloaded from Gut, 1986, 27, 339-349 Progress report Haemostatic problems in liver disease The liver plays a major role in the control of coagulation and as a result haemostatic problems are detected in approximately 75% of patients with liver disease.1 The coagulation abnormalities are both complex and multifactorial and depend on the balance between hepatic synthesis and clearance of activated coagulation proteins and their inhibitors; the presence or absence of dysfibrinogenaemia; thrombocytopenia, abnormal platelet function, and disseminated intravascular coagulation. Some patients will present with petechiae, ecchymosis or epistaxis, but most patients are asymptomatic or only bleed after venepuncture or liver biopsy. Alternatively haemorrhage may be life threatening and patients may die from variceal bleeding or from disseminated intravascular coagulation. The reasons for this disparity are not yet clear, but after the introduction of newer techniques, in particular the development of immunological assays for the antigens of coagulation proteins, our understanding of these problems has improved. The normal coagulation and fibrinolytic systems are depicted in Figures 1 and 2 while the major .__Intrinsic___ _ pathwY http://gut.bmj.com/ Kallikrein.o- PK | HMWKq 8t XII -*xiiXIIa_4------- ATIII ~ ~ 'I L1HMWK - XI* Xla %' xC-a; --------- -- on September 28, 2021 by guest. Protected copyright. IX - IXa VII -e'VIIca Extrinsic pathway [X VIII a Ce X P'okin C ATIII Ca+ XIII Common mI ~V PL II a pathway I XIIIa Fibrinogen - Fibrin Fig. 1 The coagulation cascade. HMWK=high molecular weight Kinogen, PK=Pre-Kallikrein, A TIII=antithrornbin III, PL=platelets, Ca" = Calcium, TF=tissue factor, -t- =proteolytic activation, -+=conversion ofcoagulation protein, -- -+=inhibition by plasma inhibitors, tit =crosslinking, a=activated coagulation enzyme.
  • The Underrecognized Prothrombotic Vascular Disease of COVID-19

    The Underrecognized Prothrombotic Vascular Disease of COVID-19

    Journal Articles 2020 The underrecognized prothrombotic vascular disease of COVID-19. KP Cohoon G Mahé AC Spyropoulos Zucker School of Medicine at Hofstra/Northwell, [email protected] Follow this and additional works at: https://academicworks.medicine.hofstra.edu/articles Part of the Internal Medicine Commons Recommended Citation Cohoon K, Mahé G, Spyropoulos A. The underrecognized prothrombotic vascular disease of COVID-19.. 2020 Jan 01; 4(5):Article 6487 [ p.]. Available from: https://academicworks.medicine.hofstra.edu/articles/ 6487. Free full text article. This Article is brought to you for free and open access by Donald and Barbara Zucker School of Medicine Academic Works. It has been accepted for inclusion in Journal Articles by an authorized administrator of Donald and Barbara Zucker School of Medicine Academic Works. For more information, please contact [email protected]. Received: 6 May 2020 | Revised: 16 May 2020 | Accepted: 21 May 2020 DOI: 10.1002/rth2.12396 LETTER TO THE EDITOR The underrecognized prothrombotic vascular disease of COVID-19 We have read with interest “COVID-19-associated coagulopathy around elevated markers of hypercoagulability, including D-dimer, and thromboembolic disease: Commentary on an interim expert tissue factor expression, fibrinogen levels, factor VIII levels, guidance” recently provided by Cannegieter and Klok.1 This com- short-activated partial thromboplastin time, platelet binding, and mentary exemplifies the importance that venous thromboembolism thrombin formation.8 Based on well-defined clinical and laboratory (VTE) and atheroembolism may be underrepresented and a cause parameters, a proposal for staging COVID-19 coagulopathy may for increased morbidity and mortality among coronavirus disease provide treatment algorithms stratified into 3 stages.9 However, 2019 (COVID-19) patients.