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Gold Variants: Defining a high-quality set of clinically relevant DNA variants with, and for, the Thrombosis and Hemostasis Community - Gene List

 

Overview

The SSC on Genomics in Thrombosis and Hemostasis presents a well-curated and evidence based catalogue of 91 gene-disease associations that can be used  for diagnostic genetic screening of Bleeding, Thrombotic and Platelet Disorders (BTPD) patients. Read the full communication in the Journal of Thrombosis and Haemostasis (Megy et al, 2019).  

 

Methods

Briefly, genes were included if the gene-disease association had been reported in at least 3 independent pedigrees, or <3 pedigrees and supported by linkage analysis (large pedigrees), specific functional data and/or a mouse model, and following expert discussions during yearly SSC meetings. A reference transcript was selected for each gene based on community input, transcript and protein lengths, and expression data.

 

Report of Additional Patients in TIER2 Genes

Many recent BTPD gene discoveries were made for single small pedigrees (e.g. genes PRKACG (PMID:25061177), TPM4 (PMID:28134622), TRPM7 (PMID:27020697), EPHB2 (PMID:30213874), and PTPRJ (PMID:30591527)). While those genes are relevant for BTPD diagnostics, they still require confirmation studies in independent pedigrees. Therefore, the SSC-GinTH encourages the publication of short reports describing additional pedigrees with causal variants in such novel genes to allow their upgrading to TIER1 status. 

 

For any inquiries, or to suggest a new gene, please contact the Chair of the SSC Genomics in Thrombosis and Hemostasis Subcommittee, Kathleen Freson, at: kathleen.freson@kuleuven.be

 

Gene list v.ISTH_2019: [PDF] 

Gene list v.ISTH_2019 with additional details on evidence levels and transcripts: [Excel]

 

 

Bleeding Thrombotic and Platelet Disorder TIER1 Genes

 

Category Gene symbol Associated disorder(s) Inheritance Transcript Location
Bleeding/coagulation F10 Factor X deficiency AR; AD NM_000504.3 13q34
Bleeding/coagulation F11 Factor XI deficiency AR; AD NM_000128.3 4q35.2
Coagulation
Angioedema
F12 Factor XII deficiency
Angioedema
AR (coagulation)
AD (angioedema)
NM_000505.3 5q35.3
Bleeding/coagulation F13A1 Factor XIII deficiency AR NM_000129.3 6p25.1
Bleeding/coagulation F13B Factor XIII deficiency AR NM_001994.2 1q31.3
Bleeding/coagulation
Thrombosis
F2 Prothrombin deficiency
Thrombophilia due to
thrombin defect
AR (bleeding/coagulation)
AD (thrombosis)
NM_000506.4 11p11.2
Bleeding/coagulation
Thrombosis
F5 Factor V deficiency
Thrombophilia due to activated protein C resistance
AR (bleeding/coagulation)
AD (thrombosis)
NM_000130.4 1q24.2
Bleeding/coagulation F7 Factor VII deficiency AR; AD NM_000131.4 13q34
Bleeding/coagulation F8 Haemophilia A XLR NM_000132.3 Xq28
Bleeding/coagulation F9 Haemophilia B XLR NM_000133.3 Xq27.1
Bleeding FGA Fibrinogen deficiency AR (afibrinogenemia);
AD (hypo/dysfibrinogenemia)
NM_000508.3 4q31.3
Bleeding FGB Fibrinogen deficiency AR (afibrinogenemia);
AD (hypo/dysfibrinogenemia)
NM_005141.4 4q31.3
Bleeding FGG Fibrinogen deficiency AR (afibrinogenemia);
AD (hypo/dysfibrinogenemia)
NM_021870.2 4q32.1
Bleeding/coagulation GGCX Vitamin K-dependent clotting factors deficiency 1 AR NM_000821.6 2p11.2
Coagulation KNG1 Kininogen Deficiency AR NM_000893.4 3q27.3
Bleeding/coagulation LMAN1 Combined factor V and VIII deficiency AR NM_005570.3 18q21.32
Bleeding/coagulation MCFD2 Combined factor V and VIII deficiency AR NM_139279.5 2p21
Bleeding SERPINE1 Plasminogen activator Inhibitor 1 deficiency AR; AD NM_000602.4 7q22.1
Bleeding SERPINF2 Alpha 2 antiplasmin deficiency AR NM_000934.3 17p13.3
Bleeding/coagulation VKORC1 Vitamin K-dependent clotting factors deficiency 2 AR NM_024006.5 16p11.2
Bleeding
Platelet
VWF Von Willebrand disease AD (VWD type 1 and 2)
AR (VWD type 3)
AD (VWD type 2B)
NM_000552.3 12p13.31
Thrombosis ADAMTS13 Thrombotic thrombocytopenic purpura (TTP) AR NM_139025.4 9q34.2
Thrombosis HRG Histidine-rich glycoprotein deficiency AD NM_000412.4 3q27.3
Thrombosis PIGA Paroxysmal nocturnal hemoglobinuria acquired (somatic) NM_002641.3 Xp22.2
Thrombosis PLG Plasminogen deficiency AR NM_000301.3 3q27.3
Thrombosis PROC Protein C deficiency AR; AD NM_000312.3 Xp22.2
Thrombosis PROS1 Protein S deficiency AR; AD NM_000313.3 3q27.3
Thrombosis SERPINC1 Antithrombin deficiency AR; AD NM_000488.3 1q25.1
Thrombosis SERPIND1 Heparin cofactor 2 deficiency AD NM_000185.3 22q11.21
Thrombosis
Bleeding
THBD Thrombomodulin deficiency;
Bleeding due to high soluble thrombomodulin
AD NM_000361.2 20p11.21
Platelet ABCG5 Sitosterolemia with macrothrombocytopenia AR NM_022436.2 2p21
Platelet ABCG8 Sitosterolemia with macrothrombocytopenia AR NM_022437.2 2p21
Platelet ACTB Baraitser-Winter syndrome 1 with macrothrombocytopenia AD NM_001101.3 7p22.1
Platelet ACTN1 Macrothrombocytopenia AD NM_001130004.1 14q24.1
Platelet ANKRD26 AD thrombocytopenia 2 AD NM_014915.2 10p12.1
Platelet ANO6 Scott syndrome AR NM_001025356.2 12q12
Platelet AP3B1 Hermansky-Pudlak syndrome AR NM_003664.4 5q14.1
Platelet AP3D1 Hermansky-Pudlak syndrome AR NM_001261826.3 19p13.3
Platelet ARPC1B Platelet abnormalities with eosinophilia and immune- mediated inflammatory disease AR NM_005720.4 7q22.1
Platelet BLOC1S3 Hermansky-Pudlak syndrome AR NM_212550.4 19q13.32
Platelet BLOC1S6 Hermansky-Pudlak syndrome AR NM_012388.3 15q21.1
Platelet CDC42 Takenouchi-Kosaki syndrome with thrombocytopenia AD NM_001791.4 1p36.12
Platelet CYCS AD thrombocytopenia 4 AD NM_018947.5 7p15.3
Platelet DIAPH1 Macrothrombocytopenia and sensorineural hearing loss AD NM_001079812.2 5q31.3
Platelet DTNBP1 Hermansky-Pudlak syndrome AR NM_032122.4 6p22.3
Platelet ETV6 Thrombocytopenia and susceptibility to cancer AD NM_001987.4 12p13.2
Platelet FERMT3 Leukocyte integrin adhesion deficiency, type 3 AR NM_178443.2 11q13.1
Platelet FLI1 Paris-Trousseau and Jacobson syndrome AR; AD NM_002017.4 11q24.3
Platelet FLNA Syndrome with macrothrombocytopenia XLD; XLR NM_001110556.2 Xq28
Platelet FYB1 Thrombocytopenia 3 AR NM_001465.6 5p13.1
Platelet GATA1 X-linked thrombocytopenia with dyserythropoiesis XR NM_002049.3 Xp11.23
Platelet GFI1B Platelet-type bleeding disorder 17 AD; AR NM_004188.5 9q34.13
Platelet GNE Myopathy associated with Thrombocytopenia AR NM_005476.6 9p13.3
Platelet GP1BA Bernard-Soulier syndrome; 
Mild macrothrombocytopenia;
Platelet-type von Willebrand disease
AR (BSS)
AD (mild macrothrombocytopenia)
AD (platelet-type von Willebrand)
NM_000173.5 17p13.2
Platelet GP1BB Bernard-Soulier syndrome Mild macrothrombocytopenia AR (BSS)
AD (mild macrothrombocytopenia)
NM_000407.4 22q11.21
Platelet GP6 Bleeding diathesis due to glycoprotein VI deficiency AR NM_016363.5 19q13.42
Platelet GP9 Bernard-Soulier syndrome AR NM_000174.4 3q21.3
Platelet HOXA11 Amegakaryocytic thrombocytopenia with radioulnar synostosis AD NM_005523.5 7p15.2
Platelet HPS1 Hermansky-Pudlak syndrome AR NM_000195.4 10q24.2
Platelet HPS3 Hermansky-Pudlak syndrome AR NM_032383.4 3q24
Platelet HPS4 Hermansky-Pudlak syndrome AR NM_022081.5 22q12.1
Platelet HPS5 Hermansky-Pudlak syndrome AR NM_181507.1 11p15.1
Platelet HPS6 Hermansky-Pudlak syndrome AR NM_024747.5 10q24.32
Platelet ITGA2B Glanzmann thrombasthenia
Platelet-type bleeding disorder 16
AR (GT)
AD (bleeding disorder)
NM_000419.3 17q21.31
Platelet ITGB3 Glanzmann thrombasthenia
Platelet-type bleeding
disorder 16
AR (GT)
AD (bleeding disorder)
NM_000212.2 17q21.32
Platelet KDSR Thrombocytopenia and erythrokeraderma AR NM_002035.4 18q21.33
Platelet LYST Chediak-Higashi syndrome AR NM_000081.3 1q42.3
Platelet MECOM Amegakaryocytic thrombocytopenia with radioulnar synostosis 2 AD NM_004991.3 3q26.2
Platelet MPIG6B Thrombocytopenia, anaemia and myelofibrosis AR NM_025260.3 6p21.33
Platelet MPL Congenital amegakaryocytic thrombocytopenia AR NM_005373.2 1p34.2
Platelet MYH9 MYH9-related disorders AD NM_002473.5 22q12.3
Platelet NBEA Autism with platelet dense granule defect AD NM_015678.4 13q13.3
Platelet NBEAL2 Gray platelet syndrome AR NM_015175.2 3p21.31
Platelet P2RY12 ADP receptor defect AR NM_022788.4 3q25.1
Platelet PLA2G4A Deficiency of phospholipase A2, group IV A AR NM_024420.2 1q31.1
Platelet PLAU Quebec platelet disorder AD NM_002658.3 10q22.2
Platelet RASGRP2 Platelet-type bleeding disorder 18 AR NM_153819.1 11q13.1
Platelet RBM8A Thrombocytopenia-absent radius syndrome AR NM_005105.4 1q21.1
Platelet RNU4ATAC Roifman Syndrome AR NR_023343.1 2q14.2
Platelet RUNX1 Familial platelet disorder with predisposition to AML AD NM_001754.4 21q22.12
Platelet SLFN14 Platelet-type bleeding disorder 20 AD NM_001129820.1 17q12
Platelet SRC Thrombocytopenia 6 AD NM_198291.2 20q11.23
Platelet STIM1 Stormorken syndrome (York platelet syndrome) AD NM_003156.3 11p15.4
Platelet STXBP2 Familial hemophagocytic lymphohistiocytosis type 5 AR NM_006949.2 19p13.2
Platelet TBXA2R Thromboxane A2 receptor defect AR; AD (partial phenotype) NM_001060.5 19p13.3
Platelet TBXAS1 Ghosal syndrome AR NM_030984.3 7q34
Platelet THPO Thrombocytopenia progressing to trilineage bone marrow failure AR NM_000460.4 3q27.1
Platelet TUBB1 Macrothrombocytopenia AD NM_030773.3 20q13.32
Platelet VIPAS39 Arthrogryposis, renal dysfunction, and cholestasis 1 AR NM_001193315.1 14q24.3
Platelet VPS33B Arthrogryposis, renal dysfunction, and cholestasis 2 AR NM_018668.4 15q26.1
Platelet WAS Wiskott-Aldrich syndrome XLR NM_000377.2 Xp11.23

*AD: autosomal dominant. AR: autosomal recessive. XLD: X-linked dominant. XLR: X-linked recessive. Categories in italics indicate a rarer occurrence for a specific gene.

 

Please click here to view the ISTH communications.

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