Severe Combined Immunodeficiency Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: IM0101

The Blueprint Genetics Severe Combined Immunodeficiency Panel is a 68 gene test for genetic diagnostics of patients with clinical suspicion of combined immunodeficiencies.

Approximately half of the cases with severe combined immunodeficiencies (SCIDs) are inherited in X-linked manner (IL2RG), while the inheritance is autosomal recessive for the other half. In addition to typical severe combined immunodeficiencies, this Panel has differential diagnostics power to several other combined immunodeficiencies generally less profound than SCIDs. This Panel is included in the comprehensive Primary Immunodeficiency Panel.

About Severe Combined Immunodeficiency

SCIDs are a group of primary immunodeficiencies characterized by specific mutations in genes of T and B-lymphocyte systems and leading to little or no immune response. Different subtypes of SCIDs are characterized and subdivided by the presence of circulating T and B cells. T cells are abscent or markedly decreased in the most types, but levels of B cells may be vary. In addition, both these disease subgroups (T-B+ and T-B-) can occur with or without NK cells. Patients with SCID are susceptible to recurrent infections, that can be fatal. Worldwide prevalence of SCID is estimated to be at least 1:100 000 births, while some genetically more homogenous populations may show markedly increased numbers. Mutations in IL2RG are the most common reason for SCIDs, explaining circa 50% of all cases and close to 100% of X-linked cases.

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 Severe Combined Immunodeficiency Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ADA Severe combined immunodeficiency due to adenosine deaminase deficiency AR 38 87
AK2 Reticular dysgenesis AR 14 17
ATM Breast cancer, Ataxia-Telangiectasia AD/AR 646 923
BLM Bloom syndrome AR 83 91
CARD11 B-cell expansion with NFKB and T-cell anergy, Immunodeficiency AD/AR 10 8
CD3D Immunodeficiency AR 3 5
CD3E Immunodeficiency AR 3 7
CD3G Immunodeficiency AR 3 3
CD8A CD8 deficiency AR 1 1
CD27 Lymphoproliferative syndrome AR 2 8
CD40 Immunodeficiency with Hyper-IgM AR 5 9
CD40LG Immunodeficiency, with hyper-IgM XL 27 227
CD247 Immunodeficiency AR 7 4
CIITA Bare lymphocyte syndrome AR 7 14
CORO1A* Immunodeficiency AR 38 6
DCLRE1C* Omenn syndrome, Severe combined immunodeficiency with sensitivity to ionizing radiation AR 16 83
DNMT3B Immunodeficiency-centromeric instability-facial anomalies syndrome AR 15 44
DOCK8 Hyper-IgE recurrent infection syndrome AR 34 151
IFNGR1 Immunodeficiency AD/AR 15 39
IKBKG* Incontinentia pigmenti, Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency, Immunodeficiency, Invasive pneumococcal disease, recurrent, isolated, Osteopetrosis with ectodermal dysplasia and immune defect (OLEDAID) XL 43 143
IL2RA Interleukin 2 receptor, alpha, deficiency AR 5 6
IL2RG Combined immunodeficiency XL 39 220
IL7R Severe combined immunodeficiency, , T-cell negative, B-cell positive, NK cell positive AR 19 47
IL12RB1 Immunodeficiency AR 9 81
ITGB2 Leukocyte adhesion deficiency AR 33 114
ITK Lymphoproliferative syndrome AR 3 10
JAK3 Severe combined immunodeficiency, , T cell-negative, B cell-positive, natural killer cell-negative AR 27 63
LCK Immunodeficiency AR 2 3
LIG4 Severe combined immunodeficiency with sensitivity to ionizing radiation, LIG4 syndrome AR 14 35
LRBA Common variable immunodeficiency AR 14 58
MAGT1 Immunodeficiency, with magnesium defect, Epstein-Barr virus infection and neoplasia XL 5 14
MALT1 Immunodeficiency AR 3 5
NHEJ1 Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation AR 14 15
ORAI1 Immunodeficiency AR 8 12
PIK3CD* Immunodeficiency AD 5 11
PMS2* Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposis AD/AR 196 284
PNP Purine nucleoside phosphorylase deficiency AR 10 33
PRKDC Immunodeficiency AR 6 7
PTPRC Severe combined immunodeficiency, , T-cell negative, B-cell positive, NK cell positive AR 4 5
RAG1 Omenn syndrome, Alpha/beta T-cell lymphopenia with gamma/delta T-cell expansion, severe cytomegalovirus infection, and autoimmunity, T cell-negative, B cell-negative, natural killer cell-positive severe combined immunodeficiency, Combined cellular and humoral immune defects with granulomas AR 43 181
RAG2 Omenn syndrome, Combined cellular and humoral immune defects with granulomas AR 22 78
RFX5 Bare lymphocyte syndrome AR 5 6
RFXANK MHC class II deficiency AR 6 14
RFXAP Bare lymphocyte syndrome AR 5 7
RHOH T-cell immunodeficiency with epidermodysplasia verruciformis AD/AR 1
RMRP Cartilage-hair hypoplasia, Metaphyseal dysplasia without hypotrichosis, Anauxetic dysplasia AR 29 123
RTEL1 Pulmonary fibrosis and/or bone marrow failure, Dyskeratosis congenita AD/AR 32 44
SH2D1A Lymphoproliferative syndrome XL 14 125
SMARCAL1 Schimke immunoosseous dysplasia AR 12 75
SP110 Hepatic venoocclusive disease with immunodeficiency AR 7 7
SPINK5 Netherton syndrome AR 18 82
STAT1 Immunodeficiency AD/AR 31 116
STAT2 Immunodeficiency AR 2 6
STAT3 Hyper-IgE recurrent infection syndrome, Autoimmune disease, multisystem, infantile onset AD 43 145
STAT4 Behçet disease, Juvenile rheumatoid factor-negative polyarthritis, Oligoarticular juvenile arthritis, Pediatric systemic lupus erythematosus AD/AR
STAT5B* Growth hormone insensitivity with immunodeficiency AR 5 10
STIM1 Stormorken syndrome, Immunodeficiency AD/AR 12 20
STK4 T-cell immunodeficiency syndrome, recurrent infections, autoimmunity, AR 3 7
TAP1 Bare lymphocyte syndrome AR 2 7
TAP2 Bare lymphocyte syndrome AR 2 8
TAPBP Bare lymphocyte syndrome AR 1 2
TBX1 Conotruncal anomaly face syndrome AD 11 62
TNFRSF4 Immunodeficiency AR 1
TRAC T-cell receptor-alpha/beta deficiency AR 1 1
TYK2 Immunodeficiency AR 7 8
UNC119 Immunodeficiency AR 1 5
WAS Neutropenia, severe congenital, Thrombocytopenia, Wiskott-Aldrich syndrome XL 44 431
ZAP70 Selective T-cell defect AR 13 26

*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
ATM Chr11:108098321 c.-30-1G>T NM_000051.3 rs869312754
ATM Chr11:108141209 c.2839-579_2839-576delAAGT NM_000051.3
ATM Chr11:108179837 c.5763-1050A>G NM_000051.3 rs774925473
DOCK8 Chr9:368196 c.1797+61A>C NM_203447.3 rs786205596
DOCK8 Chr9:271626 c.54-1G>T NM_203447.3 rs192864327
PRKDC Chr8:48844056 c.1777-710dupA NM_006904.6 rs760771518
ZAP70 Chr2:98349927 c.838-80G>A NM_001079.3 rs113994173

The strengths of this test include:

  • Blueprint Genetics is one of the few laboratories worldwide with CAP and ISO-15189 accreditation for NGS panels and CLIA certification
  • Superior sequencing quality
  • Careful selection of genes based on current literature, our experience and the most current mutation databases
  • Transparent and easy access to quality and performance data at the patient level that are accessible via our Nucleus portal
  • Transparent and reproducible analytical validation for each panel (see Test performance section; for complete details, see our Analytic Validation)
  • Sequencing and high resolution del/dup analysis available in one test
  • Inclusion of non-coding disease causing variants where clinically indicated (please see individual Panel descriptions)
  • Interpretation of variants following ACMG variant classification guidelines
  • Comprehensive clinical statement co-written by a PhD geneticist and a clinician specialist

 

This test does not detect the following:

  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Variants in regulatory or non-coding regions of the gene unless otherwise indicated (please see Non-coding disease causing variants covered by the panel). This mean for instance intronic variants locating deeper than 15 nucleotides from the exon-intron boundary.

 

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
  • Disorders caused by long repetitive sequences (e.g. trinucleotide repeat expansions)

 

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.

Blueprint Genetics offers a comprehensive Severe Combined Immunodeficiency Panel that covers classical genes associated with CD40 ligand deficiency, combined immunodeficiencies, complement receptor 3 deficiency, DOCK8 deficiency, Job’s syndrome, Omenn syndrome, purine nucleoside phosphorylase PNP deficiency, STAT deficiencies 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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ICD & CPT codes

CPT codes

SEQ 81479
DEL/DUP 81479


ICD codes

Commonly used ICD-10 codes when ordering the Severe Combined Immunodeficiency Panel

ICD-10 Disease
D81.9 Combined immunodeficiencies

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.

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