Severe Combined Immunodeficiency 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: 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.

Genes in the Severe Combined Immunodeficiency Panel and their clinical significance
GeneAssociated phenotypesInheritanceClinVarHGMD
ADASevere combined immunodeficiency due to adenosine deaminase deficiencyAR3588
AK2Reticular dysgenesisAR1417
ATMBreast cancer, Ataxia-TelangiectasiaAD/AR455853
BLMBloom syndromeAR5392
CARD11B-cell expansion with NFKB and T-cell anergy, ImmunodeficiencyAD/AR68
CD3DImmunodeficiencyAR34
CD3EImmunodeficiencyAR34
CD3GImmunodeficiencyAR34
CD8ACD8 deficiencyAR11
CD27Lymphoproliferative syndromeAR26
CD40Immunodeficiency with Hyper-IgMAR413
CD40LGImmunodeficiency, with hyper-IgMXL21227
CD247ImmunodeficiencyAR66
CIITABare lymphocyte syndromeAR617
CORO1A*ImmunodeficiencyAR326
DCLRE1C*Omenn syndrome, Severe combined immunodeficiency with sensitivity to ionizing radiationAR1676
DNMT3BImmunodeficiency-centromeric instability-facial anomalies syndromeAR1246
DOCK8Hyper-IgE recurrent infection syndromeAR28135
IFNGR1ImmunodeficiencyAD/AR1544
IKBKG*Incontinentia pigmenti, Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency, Immunodeficiency, Invasive pneumococcal disease, recurrent, isolatedXL30141
IL2RAInterleukin 2 receptor, alpha, deficiencyAR513
IL2RGCombined immunodeficiencyXL27215
IL7RSevere combined immunodeficiency, , T-cell negative, B-cell positive, NK cell positiveAR1542
IL12RB1ImmunodeficiencyAR885
ITGB2Leukocyte adhesion deficiencyAR27114
ITKLymphoproliferative syndromeAR310
JAK3Severe combined immunodeficiency, , T cell-negative, B cell-positive, natural killer cell-negativeAR1356
LCKImmunodeficiencyAR21
LIG4Severe combined immunodeficiency with sensitivity to ionizing radiation, LIG4 syndromeAR836
LRBACommon variable immunodeficiencyAR1045
MAGT1Immunodeficiency, with magnesium defect, Epstein-Barr virus infection and neoplasiaXL410
MALT1ImmunodeficiencyAR34
NHEJ1Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiationAR813
ORAI1ImmunodeficiencyAR711
PIK3CD*ImmunodeficiencyAD44
PMS2*Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposisAD/AR151266
PNPPurine nucleoside phosphorylase deficiencyAR1034
PRKDCImmunodeficiencyAR56
PTPRCSevere combined immunodeficiency, , T-cell negative, B-cell positive, NK cell positiveAR48
RAG1Omenn 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 granulomasAR35168
RAG2Omenn syndrome, Combined cellular and humoral immune defects with granulomasAR1866
RFX5Bare lymphocyte syndromeAR56
RFXANKMHC class II deficiencyAR612
RFXAPBare lymphocyte syndromeAR57
RHOHT-cell immunodeficiency with epidermodysplasia verruciformisAD/AR1
RMRPCartilage-hair hypoplasia, Metaphyseal dysplasia without hypotrichosis, Anauxetic dysplasiaAR24119
RTEL1Pulmonary fibrosis and/or bone marrow failure, Dyskeratosis congenitaAD/AR2726
SH2D1ALymphoproliferative syndromeXL14120
SMARCAL1Schimke immunoosseous dysplasiaAR970
SP110Hepatic venoocclusive disease with immunodeficiencyAR710
SPINK5Netherton syndromeAR884
STAT1ImmunodeficiencyAD/AR28106
STAT2ImmunodeficiencyAR24
STAT3Hyper-IgE recurrent infection syndrome, Autoimmune disease, multisystem, infantile onsetAD27133
STAT4Behçet disease, Juvenile rheumatoid factor-negative polyarthritis, Oligoarticular juvenile arthritis, Pediatric systemic lupus erythematosusAD/AR3
STAT5B*Growth hormone insensitivity with immunodeficiencyAR511
STIM1Stormorken syndrome, ImmunodeficiencyAD/AR1019
STK4T-cell immunodeficiency syndrome, recurrent infections, autoimmunity,AR36
TAP1Bare lymphocyte syndromeAR28
TAP2Bare lymphocyte syndromeAR213
TAPBPBare lymphocyte syndromeAR13
TBX1Conotruncal anomaly face syndromeAD759
TNFRSF4ImmunodeficiencyAR12
TRACT-cell receptor-alpha/beta deficiencyAR11
TYK2ImmunodeficiencyAR614
UNC119ImmunodeficiencyAR14
WASNeutropenia, severe congenital, Thrombocytopenia, Wiskott-Aldrich syndromeXL32429
ZAP70Selective T-cell defectAR1020
  • * 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 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.

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


ICD codes

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

ICD-10Disease
D81Combined 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.