- Is a 128 gene panel that includes assessment of non-coding variants
Is ideal for patients with a clinical suspicion of inherited bone marrow failure syndromes. The genes on this panel are included in the Comprehensive Hematology Panel.
Number of genes128
CPT codesSEQ 81216
The Blueprint Genetics Bone Marrow Failure Syndrome Panel (test code HE0801):
- Is a 128 gene panel that includes assessment of selected non-coding disease-causing variants
- Is available as PLUS analysis (sequencing analysis and deletion/duplication analysis), sequencing analysis only or deletion/duplication analysis only
- EDTA blood, min. 1 ml
- Purified DNA, min. 3μg
- Saliva (Oragene DNA OG-500 kit)
Label the sample tube with your patient’s name, date of birth and the date of sample collection.
Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.
Inherited bone marrow failure syndromes (IBMFS) are a diverse set of genetic disorders characterized by the inability of the bone marrow to produce sufficient circulating blood cells. Bone marrow failure can affect all blood cell lineages causing clinical symptoms similar to aplastic anemia, or be restricted to one or two blood cell lineages. The clinical presentation may include thrombocytopenia or neutropenia. Hematological manifestations may be accompanied by physical features such as short stature and abnormal skin pigmentation in Fanconi anemia and dystrophic nails, lacy reticular pigmentation and oral leukoplakia in dyskeratosis congenita. Patients with IBMFS have an increased risk of developing cancer—either hematological or solid tumors. Early and correct disease recognition is important for management and surveillance of the diseases. Currently, accurate genetic diagnosis is essential to confirm the clinical diagnosis. The most common phenotypes that are covered by the panel are Fanconi anemia, Diamond-Blackfan anemia, dyskeratosis congenita, Shwachman-Diamond syndrome and WAS-related disorders.
Genes in the Bone Marrow Failure Syndrome Panel and their clinical significance
|ACD||Dyskeratosis congenita, autosomal dominant 6, Dyskeratosis congenita, autosomal recessive 7||AD/AR||2||8|
|ATM||Breast cancer, Ataxia-Telangiectasia||AD/AR||860||1026|
|ATR||Cutaneous telangiectasia and cancer syndrome, Seckel syndrome||AD/AR||8||18|
|BRAF*||LEOPARD syndrome, Noonan syndrome, Cardiofaciocutaneous syndrome||AD||135||65|
|BRCA1*||Pancreatic cancer, Breast-ovarian cancer, familial||AD||2560||2361|
|BRCA2||Fanconi anemia, Medulloblastoma, Glioma susceptibility, Pancreatic cancer, Wilms tumor, Breast-ovarian cancer, familial||AD/AR||2959||2364|
|BRIP1||Fanconi anemia, Breast cancer||AD/AR||182||166|
|CBL||Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia||AD||23||38|
|CDKN2A||Melanoma, familial, Melanoma-pancreatic cancer syndrome||AD||81||230|
|CEBPA||Acute myeloid leukemia, familial||AD||15||10|
|CLPB||3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MEGCANN)||AR||25||25|
|CSF2RA*||Surfactant metabolism dysfunction, pulmonary||XL||2||17|
|CTC1||Cerebroretinal microangiopathy with calcifications and cysts||AR||16||30|
|CTSC||Periodontitis, juvenile, Haim-Munk syndrome, Papillon-Lefevre syndrome||AR||16||92|
|CXCR4||Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome||AD||5||15|
|DDX41||Familial myeloproliferative/lymphoproliferative neoplasms, multiple types, susceptibility to||AD||8||14|
|DKC1||Hoyeraal-Hreidarsson syndrome, Dyskeratosis congenita||XL||47||71|
|DNAJC21||Bone marrow failure syndrome 3||AR||5||8|
|EPCAM||Diarrhea 5, with tufting enteropathy, congenital, Colorectal cancer, hereditary nonpolyposis||AD/AR||26||75|
|ERCC4||Fanconi anemia, Xeroderma pigmentosum, XFE progeroid syndrome||AR||11||59|
|ERCC6L2||Bone marrow failure syndrome 2||AR||4||2|
|FADD||Infections, recurrent, with encephalopathy, hepatic dysfunction, and cardiovascular malformations||AR||2||1|
|FAS||Autoimmune lymphoproliferative syndrome||AD/AR||28||131|
|FASLG||Autoimmune lymphoproliferative syndrome, type IB||AD||3||9|
|G6PC3||Neutropenia, severe congenital, Dursun syndrome||AR||12||37|
|GATA1||Anemia, without thrombocytopenia, Thrombocytopenia with beta-thalessemia,, Dyserythropoietic anemia with thrombocytopenia||XL||19||15|
|GATA2||Myelodysplastic syndrome, Chronic neutropenia associated with monocytopenia, evolving to myelodysplasia and acute myeloid leukemia, Acute myeloid leukemia, Emberger syndrome, Immunodeficiency||AD||26||105|
|GFI1||Neutropenia, severe congenital, 2 autosomal dominant, Neutropenia, nonimmune chronic idiopathic, of adults||AD||2||5|
|HAX1||Neutropenia, severe congenital||AR||9||19|
|HRAS||Costello syndrome, Congenital myopathy with excess of muscle spindles||AD||41||29|
|IKZF1#||Immunodeficiency, common variable, 13||AD||7||12|
|JAGN1||Neutropenia, severe congenital||AR||8||8|
|KRAS*||Noonan syndrome, Cardiofaciocutaneous syndrome||AD||61||34|
|LAMTOR2||Immunodeficiency due to defect in MAPBP-interacting protein||AR||1||1|
|MAGT1||Immunodeficiency, with magnesium defect, Epstein-Barr virus infection and neoplasia, Mental retardation, X-linked 95||XL||5||14|
|MLH1||Muir-Torre syndrome, Endometrial cancer, Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposis||AD/AR||829||1174|
|MPL||Thrombocythemia, Amegakaryocytic thrombocytopenia||AD/AR||22||50|
|MSH2||Muir-Torre syndrome, Endometrial cancer, Colorectal cancer, hereditary nonpolyposis,, Mismatch repair cancer syndrome||AD/AR||874||1224|
|MSH6||Endometrial cancer, Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposis||AD/AR||580||569|
|NBN||Breast cancer, Nijmegen breakage syndrome||AD/AR||141||87|
|NF1*||Watson syndrome, Neurofibromatosis, Neurofibromatosis-Noonan syndrome||AD||810||2703|
|PALB2||Fanconi anemia, Pancreatic cancer, Breast cancer||AD/AR||422||358|
|PAX5||Pre-B cell acute lymphoblastic leukemia||AD||5|
|PMS2*||Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposis||AD/AR||259||324|
|PRF1||Lymphoma, non-Hodgkin, Aplastic anemia, adult-onset, Hemophagocytic lymphohistiocytosis||AR||22||172|
|PTPN11||Noonan syndrome, Metachondromatosis||AD||128||139|
|RAB27A||Griscelli syndrome, Elejalde syndrome||AR||17||53|
|RAC2||Neutrophil immunodeficiency syndrome||AD||2||3|
|RAD51C||Fanconi anemia, Breast-ovarian cancer, familial||AD/AR||92||112|
|RBM8A*,#||Thrombocytopenia - absent radius||AD/AR||4||10|
|RECQL4||Baller-Gerold syndrome, RAPADILINO syndrome, Rothmund-Thomson syndrome||AR||53||100|
|RTEL1||Pulmonary fibrosis and/or bone marrow failure, Dyskeratosis congenita||AD/AR||33||45|
|RUNX1||Platelet disorder, familial, with associated myeloid malignancy||AD||25||92|
|SAMD9||Mirage syndrome, Tumoral calcinosis, normophosphatemic||AR||7||17|
|SBDS*||Aplastic anemia, Shwachman-Diamond syndrome, Severe spondylometaphyseal dysplasia||AD/AR||21||90|
|SLC37A4||Glycogen storage disease||AR||29||109|
|SMARCD2||Specific granule defiency 2||AR||3||1|
|SRP72*||Bone marrow failure syndrome 1||AD||2||2|
|STX11||Hemophagocytic lymphohistiocytosis, familial||AR||6||18|
|STXBP2||Hemophagocytic lymphohistiocytosis, familial||AR||9||69|
|TERC||Aplastic anemia, Pulmonary fibrosis and/or bone marrow failure, telomere-related, Dyskeratosis congenita||AD||38||67|
|TERT||Aplastic anemia, Pulmonary fibrosis and/or bone marrow failure, telomere-related, Dyskeratosis congenita||AD/AR||43||152|
|TINF2||Revesz syndrome, Dyskeratosis congenita||AD||23||37|
|TP53||Colorectal cancer, Li-Fraumeni syndrome, Ependymoma, intracranial, Choroid plexus papilloma, Breast cancer, familial, Adrenocortical carcinoma, Osteogenic sarcoma, Hepatoblastoma, Non-Hodgkin lymphoma||AD||372||481|
|UNC13D||Hemophagocytic lymphohistiocytosis, familial||AR||15||156|
|USB1||Poikiloderma with neutropenia||AR||23||22|
|VPS45||Neutropenia, severe congenital, 5, autosomal recessive||AR||3||4|
|WAS||Neutropenia, severe congenital, Thrombocytopenia, Wiskott-Aldrich syndrome||XL||53||435|
|WIPF1||Wiskott-Aldrich syndrome 2||AR||2||2|
|XRCC2||Hereditary breast cancer||AD/AR||10||20|
* Some, or all, of the gene is 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).
The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#)
Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), 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 Orphanet databases.
Non-coding variants covered by the panel
|Gene||Genomic location HG19||HGVS||RefSeq||RS-number|
Added and removed genes from the panel
|Genes added||Genes removed|
|ACD ANKRD26 BRAF BRCA1 CBL CLPB CSF3R DDX41 DNAJC21 EPCAM ERCC6L2 ETV6 FADD FASLG GFI1 GINS1 IKZF1 LAMTOR2 MAP2K1 MAP2K2 MKL1 PAX5 PGM3 RAC2 RBM8A RIT1 SAMD9 SAMD9L SLC37A4 SMARCD2 SOS1 SRP72 THPO VPS13B VPS45 WDR1 WIPF1||RPS17 TCIRG1|
Test strengthThe strengths of this test include:
- CAP and ISO-15189 accreditations covering all operations at Blueprint Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
- CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
- Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
- Careful construction of clinically effective and scientifically justified gene panels
- Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
- Our publically available analytic validation demonstrating complete details of test performance
- ~1,500 non-coding disease causing variants in Blueprint WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
- Our rigorous variant classification based on modified ACMG variant classification scheme
- Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
- Our comprehensive clinical statements
The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: IKZF1 (4, 6, 7, 8), PMS2 (15), RBM8A (3), RPL15 (5). Genes with suboptimal coverage in our assay are marked with number sign (#) and genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk (*) if they overlap with the UCSC pseudogene regions. Gene is considered to have suboptimal coverage when >90% of the gene's target nucleotides are not covered at >20x with mapping quality score (MQ>20) reads. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).This test does not detect the following:
- Complex inversions
- Gene conversions
- Balanced translocations
- Mitochondrial DNA variants
- Repeat expansion disorders unless specifically mentioned
- Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).
This test may not reliably detect the following:
- Low level mosaicism
- Stretches of mononucleotide repeats
- Indels larger than 50bp
- Single exon deletions or duplications
- Variants within pseudogene regions/duplicated segments
The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.
For additional information, please refer to the Test performance section and see our Analytic Validation.
The Blueprint Genetics bone marrow failure syndrome panel covers classical genes associated with Hermansky-Pudlak syndrome, Diamond-Blackfan anemia, Fanconi anemia, Wiskott-Aldrich syndrome, Bloom syndrome, ELANE-related neutropenia, Shwachman-Diamond syndrome, Inherited bone marrow failure syndrome, familial hemophagocytic lymphohistiocytosis, severe congenital neutropenia and dyskeratosis congenita. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.
Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).
Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. Blueprint Genetics' Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient's phenotype is suggestive of a specific mutation type.
Performance of Blueprint Genetics Whole Exome Sequencing (WES) assay. All individual panels are sliced from WES data.
|Sensitivity % (TP/(TP+FN)||Specificity %|
|Single nucleotide variants||99.65% (412,456/413,893)||>99.99%|
|Insertions, deletions and indels by sequence analysis|
|1-10 bps||96.94% (17,070/17,608)||>99.99%|
|11-50 bps||99.07% (957/966)||>99.99%|
|Copy number variants (exon level dels/dups)|
|Clinical samples (small CNVs, n=52)|
|1 exon level deletion||92.3% (24/26)||NA|
|2 exons level deletion/duplication||100.0% (11/11)||NA|
|3-7 exons level deletion/duplication||93.3% (14/15)||NA|
|Microdeletion/-duplication sdrs (large CNVs, n=37))|
|Size range (0.1-47 Mb)||100% (37/37)|
|Simulated CNV detection|
|2 exons level deletion/duplication||90.98% (7,357/8,086)||99.96%|
|5 exons level deletion/duplication||98.63% (7,975/8,086)||99.98%|
|The performance presented above reached by WES with the following coverage metrics|
|Mean sequencing depth at exome level||174x|
|Nucleotides with >20x sequencing coverage (%)||99.4%|
The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. 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. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases such as, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as SIFT, PolyPhen, MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, the customer has an access to details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present. This reflects our mission to build fully transparent diagnostics where customers have easy access to crucial details of the analysis process.
We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.
Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the Blueprint Genetics Variant Classification Schemes based on the ACMG guideline 2015. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analyzed at our laboratory allowed us to further develop the industry standard.
The final step in the analysis of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant at least three times at Blueprint Genetics. Reported variants of uncertain significance are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call. Reported copy number variations with a size <10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at Blueprint Genetics.
Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, congress abstracts and mutation databases to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.
Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counseling. For eligible cases, Blueprint Genetics offers a no charge service to investigate the role of reported VUS (VUS Clarification Service).
Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratory is therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering health care provider at no additional cost.