Hereditary Leukemia 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: ON0101

The Blueprint Genetics Hereditary Leukemia Panel analyzes 25 genes associated with inherited suscebtibility to leukemia.

This Panel covers genes associated with hereditary syndromes that also confer an increased risk of leukemia. The Hereditary Leukemia Panel is suited for detecting heritable germline mutations and may not be used for the detection of somatic mutations in tumor tissue. This Panel is part of the Comprehensive Hereditary Cancer Panel, Bone Marrow Failure Syndrome Panel and Comprehensive Hematology Panel.

About Hereditary Leukemia

Inherited predisposition to hematological malignancies, namely acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and bone marrow myelodysplastic syndrome (MDS) may be associated with syndromic features, or occur as principal clinical features. MDSs and AML can occur in the context of syndromic bone marrow failure (eg. dyskeratosis congenita, severe congenital neutropenia, Fanconi anemia). Other hereditary syndromes with increased risk of leukemia include Li-Fraumeni syndrome (TP53), ataxia telangiectasia (ATM), Bloom syndrome (BLM), neurofibromatosis type 1 (NF1) and less frequently Noonan syndrome (PTPN11). Some reports have also shown an association of biallelic germline mutations in constitutional mismatch repair-deficiency syndrome genes, MLH1, MSH2, MSH6, and PMS2 with development of ALL. Isolated hematological malignancies are associated with germline mutations in RUNX1 (Familial platelet syndrome with predisposition to acute myelogenous leukemia), CEBPA (familial AML) and GATA2 (GATA2-associated syndromes). Many different genetic defects associated with development of leukemia have been described but the common underlying mechanism is dysfunctional DNA damage response. Based on a recent study, pathogenic variants in the known predisposition genes explain approximately 29% of families with inherited susceptibility to MDS/AML (PMID: 26492932).

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.

Genes in the Hereditary Leukemia Panel and their clinical significance
GeneAssociated phenotypesInheritanceClinVarHGMD
ATMBreast cancer, Ataxia-TelangiectasiaAD/AR455853
BLMBloom syndromeAR5392
BRCA2Fanconi anemia, Medulloblastoma, Glioma susceptibility, Pancreatic cancer, Wilms tumor, Breast-ovarian cancer, familialAD/AR25141791
CDKN2AMelanoma, familial, Melanoma-pancreatic cancer syndromeAD37217
CEBPAAcute myeloid leukemia, familialAD129
DKC1Hoyeraal-Hreidarsson syndrome, Dyskeratosis congenitaXL4569
ELANENeutropeniaAD30213
FANCAFanconi anemiaAR33474
GATA2Myelodysplastic syndrome, Chronic neutropenia associated with monocytopenia, evolving to myelodysplasia and acute myeloid leukemia, Acute myeloid leukemia, Emberger syndrome, ImmunodeficiencyAD1976
HRASCostello syndrome, Congenital myopathy with excess of muscle spindlesAD3026
KRAS*Noonan syndrome, Cardiofaciocutaneous syndromeAD4638
MLH1Muir-Torre syndrome, Endometrial cancer, Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposisAD/AR6701084
MSH2Muir-Torre syndrome, Endometrial cancer, Colorectal cancer, hereditary nonpolyposis,, Mismatch repair cancer syndromeAD/AR6461089
MSH6Endometrial cancer, Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposisAD/AR308426
NBNBreast cancer, Nijmegen breakage syndromeAD/AR5762
NF1*Watson syndrome, Neurofibromatosis, Neurofibromatosis-Noonan syndromeAD2612607
NRASNoonan syndromeAD178
PMS2*Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposisAD/AR151266
PTPN11LEOPARD syndrome, Noonan syndrome, MetachondromatosisAD122129
RUNX1Platelet disorder, familial, with associated myeloid malignancyAD1374
SBDS*Aplastic anemia, Shwachman-Diamond syndrome, Severe spondylometaphyseal dysplasiaAD/AR1288
TERCAplastic anemia, Pulmonary fibrosis and/or bone marrow failure, telomere-related, Dyskeratosis congenitaAD3660
TERTAplastic anemia, Pulmonary fibrosis and/or bone marrow failure, telomere-related, Dyskeratosis congenitaAD/AR39133
TINF2Revesz syndrome, Dyskeratosis congenitaAD2033
TP53Colorectal cancer, Li-Fraumeni syndrome, Ependymoma, intracranial, Choroid plexus papilloma, Breast cancer, familial, Adrenocortical carcinoma, Osteogenic sarcoma, Hepatoblastoma, Non-Hodgkin lymphomaAD148391
  • * 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 hereditary leukemia panel that covers classical genes associated with ataxia telangiectasia, Bloom syndrome, Costello syndrome, dyskeratosis congenital, familial acute myeloid leukemia caused by CEBPA mutations, familial platelet syndrome with predisposition to acute myelogenous leukemia, Fanconi anemia, leukemia, Li-Fraumeni syndrome, lynch syndrome, monocytopenia with susceptibility to infections, neurofibromatosis type 1, Noonan syndrome, severe congenital neutropenia and shwachman-Diamond 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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ICD & CPT codes

CPT codes

SEQ81479
DEL/DUP81479

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • 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.