Anemia 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: HE0401

The Blueprint Genetics Anemia Panel is a 68 gene test for genetic diagnostics of patients with clinical suspicion of hereditary anemia.

This panel is specifically designed for differential diagnosis of inherited anemias, which are a genetically and clinically heterogenous group of disorders. The panel covers genes associated with hereditary anemia, including (but not limited to) sickle cell anemia, thalassemia, Fanconi anemia, Diamond-Blackfan anemia, hemolytic anemia and pyruvate kinase deficiency. This panel is part of the Comprehensive Hematology Panel.

About Anemia

Anemia is defined as decrease in the amount of red blood cells or hemoglobin in the blood. The symptoms of anemia include fatigue, weakness, pale skin, and shortness of breath. Other more serious symptoms may occur depending on the underlying cause. The causes of anemia may be classified as impaired red blood cell (RBC) production or increased RBC destruction (hemolytic anemias). Hereditary anemia may be clinically highly variable, including mild, moderate, or severe forms. Hb Bart syndrome, that is a form of alpha thalassemias, is an example of a severe form of anemia. It is characterized by hydrops fetalis leading to death almost always in utero or shortly after birth. The thalassemias, sickle cell disease, and other hemoglobinopathies represent a major group of inherited disorders of hemoglobin synthesis (HBA1, HBA2, HBB). The thalassemias are among the most common genetic disorders worldwide, occurring more frequently in the Mediterranean region, the Indian subcontinent, Southeast Asia, and West Africa. Hereditary spherocytosis and hereditary elliptocytosis are examples of inherited hemolytic anemias. The hereditary spherocytosis is the most common congenital hemolytic anemia among Caucasians with an estimated prevalence ranging from 1:2,000 to 1:5,000.

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 Anemia Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ABCB7 Anemia, sideroblastic, and spinocerebellar ataxia XL 9 6
ADAMTS13 Schulman-Upshaw syndrome, Thrombotic thrombocytopenic purpura, familial AR 22 172
ALAS2 Anemia, sideroblastic, Protoporphyria, erythropoietic XL 27 93
AMN Megaloblastic anemia-1, Norwegian AR 24 32
ANK1 Spherocytosis AD/AR 12 82
ATM Breast cancer, Ataxia-Telangiectasia AD/AR 455 853
ATR Cutaneous telangiectasia and cancer syndrome, Seckel syndrome AD/AR 6 13
ATRX Carpenter-Waziri syndrome, Alpha-thalassemia/mental retardation syndrome, Holmes-Gang syndrome, Juberg-Marsidi syndrome, Smith-Fineman-Myers syndrome, Mental retardation-hypotonic facies syndrome XL 42 149
BLM Bloom syndrome AR 53 92
BRCA2 Fanconi anemia, Medulloblastoma, Glioma susceptibility, Pancreatic cancer, Wilms tumor, Breast-ovarian cancer, familial AD/AR 2514 1791
BRIP1 Fanconi anemia, Breast cancer AD/AR 87 87
C15ORF41 Congenital dyserythropoietic anemia AR 2
CDAN1 Anemia, dyserythropoietic congenital AR 10 43
CUBN* Megaloblastic anemia-1, Finnish AR 32 49
EPB42 Spherocytosis AR 9 12
ERCC4 Fanconi anemia, Xeroderma pigmentosum AR 11 37
FANCA Fanconi anemia AR 33 474
FANCB Fanconi anemia XL 7 14
FANCC Fanconi anemia AR 34 34
FANCD2* Fanconi anemia AR 10 49
FANCE Fanconi anemia AR 3 9
FANCF Fanconia anemia AR 6 8
FANCG Fanconi anemia AR 11 73
FANCI Fanconi anemia AR 8 27
FANCL Fanconi anemia AR 6 15
FANCM Fanconi anemia AR 1 13
G6PD Glucose-6-phosphate dehydrogenase deficiency XL 36 214
GATA1 Anemia, without thrombocytopenia, Thrombocytopenia with beta-thalessemia,, Dyserythropoietic anemia with thrombocytopenia XL 16 14
GPI Hemolytic anemia, nonspherocytic due to glucose phosphate isomerase deficiency AD 10 37
GSS Glutathione synthetase deficiency AR 7 34
HBA1* Alpha-thalassemia (Hemoglobin Bart syndrome), Alpha-thalassemia (Hemoglobin H disease) AR/Digenic 8 197
HBA2* Alpha-thalassemia (Hemoglobin Bart syndrome), Alpha-thalassemia (Hemoglobin H disease) AR/Digenic 22 279
HBB Sickle cell disease, Thalassemia-beta, dominant inclusion body, Other Thalassemias/Hemoglobinopathies, Beta-thalassemia AD/AR/Digenic 175 835
HFE Hemochromatosis AR/Digenic 7 53
KLF1 Anemia, dyserythropoietic congenital, Blood group, Lutheran inhibitor AD/BG 16 63
LPIN2 Majeed syndrome AR 8 10
MTR Methylmalonic acidemia AR 11 39
NBN Breast cancer, Nijmegen breakage syndrome AD/AR 57 62
PALB2 Fanconi anemia, Pancreatic cancer, Breast cancer AD/AR 237 223
PC Pyruvate carboxylase deficiency AR 24 39
PDHA1 Leigh syndrome, Pyruvate dehydrogenase E1-alpha deficiency XL 39 165
PDHX Pyruvate dehydrogenase E3-binding protein deficiency AR 12 22
PKLR Pyruvate kinase deficiency AR 16 240
PUS1 Mitochondrial myopathy and sideroblastic anemia AR 5 7
RAD51C Fanconi anemia, Breast-ovarian cancer, familial AD/AR 49 86
RPL5 Diamond-Blackfan anemia AD 8 66
RPL11 Diamond-Blackfan anemia AD 7 40
RPL15* Diamond-Blackfan anemia AD 2 2
RPL35A Diamond-Blackfan anemia AD 4 12
RPS7 Diamond-Blackfan anemia AD 1 8
RPS10 Diamond-Blackfan anemia AD 3 5
RPS17* Diamond-Blackfan anemia AD 4 17
RPS19 Diamond-Blackfan anemia AD 9 166
RPS24 Diamond-Blackfan anemia AD 5 9
RPS26 Diamond-Blackfan anemia AD 8 30
RPS29 Diamond-Blackfan anemia AD 2 3
SBDS* Aplastic anemia, Shwachman-Diamond syndrome, Severe spondylometaphyseal dysplasia AD/AR 12 88
SEC23B Anemia, dyserythropoietic congenital AR 12 88
SLC4A1 Spherocytosis, Ovalcytosis, Renal tubular acidosis, distal, with hemolytic anemia, Cryohydrocytosis AD/AR/BG 30 136
SLC19A2 Thiamine-responsive megaloblastic anemia syndrome AR 10 47
SLX4 Fanconi anemia AR 8 31
SPTA1 Spherocytosis, Ellipsocytosis, Pyropoikilocytosis AD/AR 21 45
SPTB Spherocytosis, Anemia, neonatal hemolytic, Ellipsocytosis AD/AR 14 66
THBD Thrombophilia due to thrombomodulin defect, Hemolytic uremic syndrome, atypical AD 5 27
TMPRSS6 Iron-refractory iron deficiency anemia AR 13 76
TPI1 Triosephosphate isomerase deficiency AR 8 19
XRCC2 Hereditary breast cancer AD/AR 3 13
YARS2 Myopathy, lactic acidosis, and sideroblastic anemia AR 19 10

*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 Anemia Panel that covers classical genes associated with alpha-thalassemia, beta-thalassemia, congenital dyserythropoietic anemia, congenital thrombotic thrombocytopenic purpura, Diamond-Blackfan anemia, Fanconi anemia, Grasbeck-Imerslund disease, Hb Bart’s hydrops fetalis, hemoglobin H disease, hemolytic anemia, hereditary anemia, hereditary elliptocytosis, hereditary spherocytosis, shwachman-Diamond syndrome, sickle cell anemia and x-linked sideroblastic anemia. 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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