Bleeding Disorder/Coagulopathy Panel

SEQmethod-seq-icon Our Sequence Analysis is based on a proprietary targeted sequencing method OS-Seq™ and offers panels targeted for genes associated with certain phenotypes. A standard way to analyze NGS data for finding the genetic cause for Mendelian disorders. Results in 21 days. DEL/DUPmethod-dup-icon Targeted Del/Dup (CNV) analysis is used to detect bigger disease causing deletions or duplications from the disease-associated genes. Results in 21 days. PLUSmethod-plus-icon Plus Analysis combines Sequence + Del/Dup (CNV) Analysis providing increased diagnostic yield in certain clinical conditions, where the underlying genetic defect may be detectable by either of the analysis methods. Results in 21 days.

Test code: HE1301

The Blueprint Genetics Bleeding Disorder/Coagulopathy Panel is a 54 gene test for genetic diagnostics of patients with clinical suspicion of inherited bleeding disorder.

This panel covers genes associated with coagulation factor deficiencies, platelet function disorders and inherited thrombocytopenias. This panel is specifically designed for differential diagnosis of various inherited bleeding disorders. Genetic diagnosis is essential in choosing the best treatment strategies. This panel comprises Coagulation Factor Deficiency Panel, Platelet Function Disorder Panel and Thrombocytopenia Panel and is included in the Comprehensive Hematology Panel.

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 is currently routinely used in the clinical care of the patients with hereditary bleeding disorder.

Availability

Results in 3-4 weeks.

Genes in the Bleeding Disorder/Coagulopathy Panel and their clinical significance
GeneAssociated phenotypesInheritanceClinVarHGMD
ABCG5SitosterolemiaAR1037
ABCG8SitosterolemiaAR1138
ACTN1Bleeding disorder, platelet-AD625
ADAMTS13Schulman-Upshaw syndrome, Thrombotic thrombocytopenic purpura, familialAR22172
ANKRD26ThrombocytopeniaAD519
AP3B1Hermansky-Pudlak syndromeAR1423
BLOC1S3Hermansky-Pudlak syndromeAR12
BLOC1S6Hermansky-Pudlak syndromeAR11
CYCS*ThrombocytopeniaAD23
DTNBP1Hermansky-Pudlak syndromeAR23
F2Thrombophilia due to thrombin defect, Prothrombin deficiency, congenitalAD/AR1466
F5Factor V deficiency, Thrombophilia due to activated protein C resistanceAD/AR18162
F7Factor VII deficiencyAR23304
F8*Hemophilia AXL2763074
F9Hemophilia B, Warfarin sensitivity, Thrombophilia, due to factor IX defectXL1091260
F10Factor X deficiencyAR15147
F11Factor XI deficiencyAD/AR35250
F12AngioedemaAD/AR553
F13A1Factor XIIIA deficiencyAR20165
FGAAfibrinogenemia, congenital, Dysfibrinogenemia, congenital, Hypodysfibrinogenemia, congenital, Familial visceral amyloidosisAD/AR9140
FGBAfibrinogenemia, congenital, Dysfibrinogenemia, congenital, Hypodysfibrinogenemia, congenitalAD/AR688
FGGAfibrinogenemia, congenital, Hypodysfibrinogenemia, Dysfibrinogenemia, congenital, Hypodysfibrinogenemia, congenitalAD/AR5127
FLNAXL86209
GATA1Anemia, without thrombocytopenia, Thrombocytopenia with beta-thalessemia,, Dyserythropoietic anemia with thrombocytopeniaXL1614
GGCXPseudoxanthoma elasticum-like disorder with multiple coagulation factor deficiency, Vitamin K-dependent clotting factors, combined deficiencyAD/AR/Digenic1338
GP1BAPseudo-von Willebrand disease, Bernard-Soulier syndromeAD/AR670
GP1BBGiant platelet disorder, isolated, Bernard-Soulier syndromeAR548
GP9Bernard-Soulier syndromeAR639
HOXA11Radioulnar synostosis with amegakaryocytic thrombocytopeniaAD11
HPS1*Hermansky-Pudlak syndromeAR2641
HPS3Hermansky-Pudlak syndromeAR813
HPS4Hermansky-Pudlak syndromeAR1415
HPS5Hermansky-Pudlak syndromeAR714
HPS6Hermansky-Pudlak syndromeAR924
ITGA2BGlanzmann thrombastheniaAR17210
ITGB3Bleeding disorder, platelet-, Thrombocytopenia, neonatal alloimmune, Glanzmann thrombastheniaAD/AR16152
LMAN1Combined factor V and VIII deficiencyAR537
MASTLThrombocytopeniaAD13
MPLThrombocythemia, Amegakaryocytic thrombocytopeniaAD/AR1450
MYH9Sebastian syndrome, May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, Macrothrombocytopenia and progressive sensorineural deafnessAD19113
NBEAL2Gray platelet syndromeAR838
P2RY12Bleeding disorder, platelet-AD/AR311
PROCThrombophilia, hereditaryAD/AR29374
PROS1*Thrombophilia, hereditaryAD/AR15409
RBM8A*Thrombocytopenia - absent radiusAD/AR47
RUNX1Platelet disorder, familial, with associated myeloid malignancyAD1374
SERPINC1Antithrombin III deficiencyAD/AR39355
SLFN14ThrombocytopeniaAD/AR45
TBXA2RBleeding disorder, platelet-AD11
THBDThrombophilia due to thrombomodulin defect, Hemolytic uremic syndrome, atypicalAD527
TUBB1MacrothrombocytopeniaAD19
VKORC1Drug metabolism, VKORC1-related, Vitamin K-dependent clotting factors, combined deficiencyAD/AR533
VWF*Von Willebrand diseaseAD/AR38857
WASNeutropenia, severe congenital, Thrombocytopenia, Wiskott-Aldrich syndromeXL32429
  • * Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Blueprint Genetics offers a comprehensive bleeding disorder/Coagulopathy panel that covers classical genes associated with Bernard-Soulier syndrome, congenital amegakaryocytic thrombocytopenia, congenital factor II deficiency, congenital factor V deficiency, congenital factor VII deficiency, congenital factor X deficiency, congenital factor XI deficiency, congenital thrombotic thrombocytopenic purpura, familial platelet syndrome with predisposition to acute myelogenous leukemia, Glanzmann thrombasthenia, gray platelet syndrome, hereditary combined deficiency of vitamin K-dependent clotting factors, Hermansky-Pudlak syndrome, inherited bleeding disorder, MYH9-related disease, severe hemophilia A, severe hemophilia B, Von Willebrand disease type 1 and Wiskott-Aldrich syndrome. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Please see our latest validation report showing sensitivity and specificity for SNPs and indels, sequencing depth, % of the nucleotides reached at least 15x coverage etc. If the Panel is not present in the report, data will be published when the Panel becomes available for ordering. Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. All the Panels available for ordering have sensitivity and specificity higher than > 0.99 to detect single nucleotide polymorphisms and a high sensitivity for indels ranging 1-19 bp. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile. Detection limit for Del/Dup analysis varies through the genome from one to six exon Del/Dups depending on exon size, sequencing coverage and sequence content.

The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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