Bleeding Disorder/Coagulopathy Panel

PLUSbpg-method 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 3–4 weeks. SEQbpg-method 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 3–4 weeks. DEL/DUPbpg-method Targeted Del/Dup (CNV) analysis is used to detect bigger disease causing deletions or duplications from the disease-associated genes. Results in 3–4 weeks.

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. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more: http://blueprintgenetics.com/faqs/#prenatal

Genes in the Bleeding Disorder/Coagulopathy Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ABCG5 Sitosterolemia AR 10 37
ABCG8 Sitosterolemia AR 11 38
ACTN1 Bleeding disorder, platelet- AD 6 25
ADAMTS13 Schulman-Upshaw syndrome, Thrombotic thrombocytopenic purpura, familial AR 22 172
ANKRD26 Thrombocytopenia AD 5 19
AP3B1 Hermansky-Pudlak syndrome AR 14 23
BLOC1S3 Hermansky-Pudlak syndrome AR 1 2
BLOC1S6 Hermansky-Pudlak syndrome AR 1 1
CYCS* Thrombocytopenia AD 2 3
DTNBP1 Hermansky-Pudlak syndrome AR 2 3
F2 Thrombophilia due to thrombin defect, Prothrombin deficiency, congenital AD/AR 14 66
F5 Factor V deficiency, Thrombophilia due to activated protein C resistance AD/AR 18 162
F7 Factor VII deficiency AR 23 304
F8* Hemophilia A XL 276 3074
F9 Hemophilia B, Warfarin sensitivity, Thrombophilia, due to factor IX defect XL 109 1260
F10 Factor X deficiency AR 15 147
F11 Factor XI deficiency AD/AR 35 250
F12 Angioedema AD/AR 5 53
F13A1 Factor XIIIA deficiency AR 20 165
FGA Afibrinogenemia, congenital, Dysfibrinogenemia, congenital, Hypodysfibrinogenemia, congenital, Familial visceral amyloidosis AD/AR 9 140
FGB Afibrinogenemia, congenital, Dysfibrinogenemia, congenital, Hypodysfibrinogenemia, congenital AD/AR 6 88
FGG Afibrinogenemia, congenital, Hypodysfibrinogenemia, Dysfibrinogenemia, congenital, Hypodysfibrinogenemia, congenital AD/AR 5 127
FLNA Frontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defects XL 86 209
GATA1 Anemia, without thrombocytopenia, Thrombocytopenia with beta-thalessemia,, Dyserythropoietic anemia with thrombocytopenia XL 16 14
GGCX Pseudoxanthoma elasticum-like disorder with multiple coagulation factor deficiency, Vitamin K-dependent clotting factors, combined deficiency AD/AR/Digenic 13 38
GP1BA Pseudo-von Willebrand disease, Bernard-Soulier syndrome AD/AR 6 70
GP1BB Giant platelet disorder, isolated, Bernard-Soulier syndrome AD/AR 5 48
GP9 Bernard-Soulier syndrome AR 6 39
HOXA11 Radioulnar synostosis with amegakaryocytic thrombocytopenia AD 1 1
HPS1* Hermansky-Pudlak syndrome AR 26 41
HPS3 Hermansky-Pudlak syndrome AR 8 13
HPS4 Hermansky-Pudlak syndrome AR 14 15
HPS5 Hermansky-Pudlak syndrome AR 7 14
HPS6 Hermansky-Pudlak syndrome AR 9 24
ITGA2B Glanzmann thrombasthenia AD/AR 17 210
ITGB3 Bleeding disorder, platelet-, Thrombocytopenia, neonatal alloimmune, Glanzmann thrombasthenia AD/AR 16 152
LMAN1 Combined factor V and VIII deficiency AR 5 37
MASTL Thrombocytopenia AD 1 3
MPL Thrombocythemia, Amegakaryocytic thrombocytopenia AD/AR 14 50
MYH9 Sebastian syndrome, May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, Macrothrombocytopenia and progressive sensorineural deafness AD 19 113
NBEAL2 Gray platelet syndrome AR 8 38
P2RY12 Bleeding disorder, platelet- AD/AR 3 11
PROC Thrombophilia, hereditary AD/AR 29 374
PROS1* Thrombophilia, hereditary AD/AR 15 409
RBM8A* Thrombocytopenia - absent radius AD/AR 4 7
RUNX1 Platelet disorder, familial, with associated myeloid malignancy AD 13 74
SERPINC1 Antithrombin III deficiency AD/AR 39 355
SLFN14 Thrombocytopenia AD/AR 4 5
TBXA2R Bleeding disorder, platelet- AD 11
THBD Thrombophilia due to thrombomodulin defect, Hemolytic uremic syndrome, atypical AD 5 27
TUBB1 Macrothrombocytopenia AD 1 9
VKORC1 Drug metabolism, VKORC1-related, Vitamin K-dependent clotting factors, combined deficiency AD/AR 5 33
VWF* Von Willebrand disease AD/AR 38 857
WAS Neutropenia, severe congenital, Thrombocytopenia, Wiskott-Aldrich syndrome XL 32 429

*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.

Gene Genomic location HG19 HGVS RefSeq RS-number Comment Reference
F2 Chr11:46761055 c.*97G>A NM_000506.4 rs1799963

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.

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. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. 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.

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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