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  • Test code: 04311
  • Turnaround time:
    10–21 calendar days (14 days on average)
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    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
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  1. Test Catalog
  2. Invitae Comprehensive Severe Combined Immunodeficiency (SCID) Panel

Invitae Comprehensive Severe Combined Immunodeficiency (SCID) Panel

Test description

The Invitae Severe Combined Immunodeficiency Panel analyzes genes that are associated with severe combined immunodeficiency (SCID). This test is useful for the diagnosis of patients who are suspected of having SCID from clinical symptoms and laboratory findings, including abnormal newborn screening, abnormal CBC with differential, and abnormal flow cytometry. Genetic testing of the genes in this panel may confirm a diagnosis and help guide treatment and management decisions.

Maternal cell engraftment has been reported in 40 – 45% of SCID cases (PMID: 8410508, 27444177, 11535520). To reduce the risk of reduced sensitivity or specificity as a result of maternal cell engraftment in SCID patients, when possible, we recommend the use of Assisted Saliva kits for SCID cases. DNA derived from saliva mostly represents granulocytes, which are not affected by maternal cell engraftment, versus lymphocytes which have higher concentration in whole blood samples. In addition, if the patient has undergone a hematopoietic stem cell transplant for SCID prior to genetic testing, the Assisted Saliva kit is also recommended as granulocytes are typically not affected by conditioning regimes used for SCID transplants. These kits work best in patients who are at least 6 months old, although successful collection has been obtained in younger patients. To obtain a kit, please use our kit request form.

Genes tested

Primary panel

ADA AK2 CD247 CD3D CD3E CORO1A DCLRE1C IL2RG IL7R JAK3 LIG4 NHEJ1 PNP PRKDC PTPRC RAG1 RAG2 ZAP70

Add-on Combined Immunodeficiency (CID) Genes

B2M BCL10 CARD11 CD27 CD3G CD40LG CD8A CIITA CTPS1 DOCK2 DOCK8 ICOS IKBKB IL21 IL21R ITK LCK LRBA MAGT1 MALT1 MAP3K14 RAC2 RFX5 RFXANK RFXAP RHOH SH2D1A STK4 TAP1 TAP2 TAPBP TNFRSF4

Recent data from newborn screening laboratories have shown that some CID patients can be identified through SCID newborn screening (PMID: 25138334). Given the immunological presentation overlap between SCID and CID and the difficulty in differentiating between SCID and CID on newborn screening assays, analyzing the CID genes may be appropriate. This gene can be included at no additional charge.

Add-on Combined Immunodeficiency (CID) with Syndromic Features Genes

ACD ATM CHD7 CTC1 DCLRE1B DKC1 DNMT3B EPG5 FOXN1 NBN NFKBIA NHP2 NOP10 ORAI1 PARN PGM3 PMS2 POLE RMRP RTEL1 SEMA3E SMARCAL1 SP110 SPINK5 STAT3 STAT5B STIM1 TBX1 TCN2 TERC TERT TINF2 TTC7A WAS WIPF1 ZBTB24

Combined immunodeficiencies (CID) with syndromic features have significant overlap of immunological findings compared to patients with non-syndromic CID. Especially at very early ages, some syndromic features may be difficult to identify or have not yet manifested. In addition, recent data from newborn screening laboratories have shown that some CID patients can be identified through SCID newborn screening (PMID: 25138334). Given the significant overlap between syndromic and non-syndromic CID as well as the ability to detect syndromic CID on SCID newborn screening, analyzing the genes associated with syndromic CID may be appropriate. These genes can be included at no additional charge.

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Primary panel (18 genes)

ADA AK2 CD247 CD3D CD3E CORO1A DCLRE1C IL2RG IL7R JAK3 LIG4 NHEJ1 PNP PRKDC PTPRC RAG1 RAG2 ZAP70

Panel details and technical assay limitations
Add-on Combined Immunodeficiency (CID) Genes (32 genes)

Recent data from newborn screening laboratories have shown that some CID patients can be identified through SCID newborn screening (PMID: 25138334). Given the immunological presentation overlap between SCID and CID and the difficulty in differentiating between SCID and CID on newborn screening assays, analyzing the CID genes may be appropriate. This gene can be included at no additional charge.

B2M BCL10 CARD11 CD27 CD3G CD40LG CD8A CIITA CTPS1 DOCK2 DOCK8 ICOS IKBKB IL21 IL21R ITK LCK LRBA MAGT1 MALT1 MAP3K14 RAC2 RFX5 RFXANK RFXAP RHOH SH2D1A STK4 TAP1 TAP2 TAPBP TNFRSF4

Panel details and technical assay limitations
Add-on Combined Immunodeficiency (CID) with Syndromic Features Genes (36 genes)

Combined immunodeficiencies (CID) with syndromic features have significant overlap of immunological findings compared to patients with non-syndromic CID. Especially at very early ages, some syndromic features may be difficult to identify or have not yet manifested. In addition, recent data from newborn screening laboratories have shown that some CID patients can be identified through SCID newborn screening (PMID: 25138334). Given the significant overlap between syndromic and non-syndromic CID as well as the ability to detect syndromic CID on SCID newborn screening, analyzing the genes associated with syndromic CID may be appropriate. These genes can be included at no additional charge.

ACD ATM CHD7 CTC1 DCLRE1B DKC1 DNMT3B EPG5 FOXN1 NBN NFKBIA NHP2 NOP10 ORAI1 PARN PGM3 PMS2 POLE RMRP RTEL1 SEMA3E SMARCAL1 SP110 SPINK5 STAT3 STAT5B STIM1 TBX1 TCN2 TERC TERT TINF2 TTC7A WAS WIPF1 ZBTB24

Panel details and technical assay limitations

Clinical information



Gene Disorder Protein name Protein symbol
ADA Adenosine deaminase (ADA) deficiency adenosine deaminase ADA
AK2 Reticular dysgenesis, AK2 deficiency adenylate kinase-2 AK2
CD247 CD3ζ deficiency CD3-zeta CD3-zeta
CD3D CD3δ deficiency CD3-delta CD3-delta
CD3E CD3ε deficiency CD3-epsilon CD3-epsilon
CORO1A Coronin-1A deficiency coronin-1A CORO1A
DCLRE1C DCLRE1C (Artemis) deficiency Artemis Artemis
IL2RG γc deficiency interleukin receptor common gamma chain gamma-c
IL7R IL7Rα deficiency interleukin 7 receptor alpha IL-7RA
JAK3 JAK3 deficiency Janus activating kinase 3 JAK3
LIG4 DNA ligase IV deficiency DNA ligase IV LIG4
NHEJ1 Cernunnos/XLF deficiency Cernunnos Cernunnos
PNP Purine nucleoside phosphorylase (PNP) deficiency purine nucleoside phosphorylase PNP
PRKDC DNA PKcs deficiency DNA-PKcs DNA-PKcs
PTPRC CD45 deficiency CD45 CD45
RAG1 RAG 1 deficiency recombinase activating gene 1 RAG1
RAG2 RAG 2 deficiency recombinase activating gene 2 RAG2
ZAP70 ZAP-70 deficiency protein tyrosine kinase ZAP70 ZAP70

Severe combined immunodeficiency syndrome (SCID) is an infantile-onset primary immunodeficiency syndrome that results in the dysfunction of both T-lymphocyte and B-lymphocyte function. Some causes of SCID may also result in defective natural killer cell function.

Children with SCID often present with severe, recurrent, and often life-threatening infections that are difficult to treat due to the patient’s compromised immune system. These infections may be caused by opportunistic organisms that are not usually infectious to children with normal immune systems; they can even be caused by vaccines made with a live virus. Patients often have persistent diarrhea, which can lead to a failure to thrive and skin involvement such as recurrent skin infections or rashes. Some patients with milder mutations in SCID-associated genes may be characterized as Omenn syndrome. Patients with Omenn syndrome develop erythroderma, hepatosplenomegaly, and lymphadenopathy in addition to immunodeficiency, and may have T-cells that function poorly. Without treatment, patients with SCID often die early in life, so early diagnosis and treatment are crucial. Many patients have been treated successfully with hematopoietic stem cell transplant.

Patients with SCID will have low lymphocyte counts using CBC with differential and abnormal findings on flow cytometry. Flow cytometry can help determine if the SCID is T-cell negative B-cell negative, in which both T-cell and B-cell numbers are greatly reduced, or can suggest T-cell negative B-cell positive SCID, in which only T-cell numbers are greatly reduced but the function of both T-cells and B-cells are compromised. In 2008, state newborn screening programs began screening for SCID, enabling early identification of babies that require further SCID evaluation.

The clinical sensitivity of this test is dependent on the patient’s underlying genetic condition. This test covers all of the common genetic causes of SCID. A minimum of 73% of individuals with characteristic features of SCID are expected to have a pathogenic variant identified in one of the genes on this panel, although exact estimates are unknown (PMID: 8410508, 9063412, 25138334).

Gene % of SCID cases attributed
ADA ~10%–15%
AK2 <1%
CD247 unknown
CD3D ~2%
CD3E unknown
CORO1A unknown
DCLRE1C ~4%
IL2RG ~20%–28%
IL7R ~12%
JAK3 ~6%–7%
LIG4 unknown
NHEJ1 unknown
PNP unknown
PRKDC unknown
PTPRC unknown
RAG1 ~16%
RAG2 ~2%
ZAP70 unknown

Many forms of SCID are autosomal recessive, though the most common cause of SCID is inherited in an X-linked manner.

According to recent newborn screening data, SCID has an estimated overall incidence rate of 1 in 58,000 in the US. Incidence is as high as 1 in 3,500 in individuals of Navajo heritage due to a founder mutation in DCLRE1C (PMID: 25138334).

This test may be considered for individuals:

  • who have abnormal newborn screening results for SCID
  • who have combined immunodeficiency in peripheral blood
  • who have a history of severe early-onset infections, but trisomy 21, DiGeorge syndrome, and other microdeletion syndromes have been ruled out

For considerations for testing please refer to:

  1. Kwan, A, et al. Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA. 2014; 312(7):729-38. PMID: 25138334
  2. Matthews, AG, et al. Compound heterozygous mutation of Rag1 leading to Omenn syndrome. PLoS ONE. 2015; 10(4):e0121489. PMID: 25849362
  3. de, la, Morena, MT, Nelson, RP. Recent advances in transplantation for primary immune deficiency diseases: a comprehensive review. Clin Rev Allergy Immunol. 2014; 46(2):131-44. PMID: 23832379
  4. Griffith, LM, et al. Allogeneic hematopoietic cell transplantation for primary immune deficiency diseases: current status and critical needs. J. Allergy Clin. Immunol. 2008; 122(6):1087-96. PMID: 18992926
  5. Baffelli, R, et al. Diagnosis, Treatment and Long-Term Follow Up of Patients with ADA Deficiency: a Single-Center Experience. J. Clin. Immunol. 2015; 35(7):624-37. PMID: 26376800
  6. Dvorak, CC, et al. Comparison of outcomes of hematopoietic stem cell transplantation without chemotherapy conditioning by using matched sibling and unrelated donors for treatment of severe combined immunodeficiency. J. Allergy Clin. Immunol. 2014; 134(4):935-943.e15. PMID: 25109802
  7. Hershfield, M. Adenosine Deaminase Deficiency. 2006 Oct 03. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301656
  8. Allenspach, E, et al. X-Linked Severe Combined Immunodeficiency. 2003 Aug 26. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301584
  9. Rosenberg, SL, Larkin, A. ZAP70-Related Severe Combined Immunodeficiency. 2009 Oct 20. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301777
  10. Mäkitie, O, Kostjukovits, S. Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders. 2012 Mar 15. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 22420014
  11. Picard, C, et al. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J. Clin. Immunol. 2015; 35(8):696-726. PMID: 26482257
  12. Shiow, LR, et al. Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2 deletion. Clin. Immunol. 2009; 131(1):24-30. PMID: 19097825
  13. Woodbine, L, et al. PRKDC mutations in a SCID patient with profound neurological abnormalities. J. Clin. Invest. 2013; 123(7):2969-80. PMID: 23722905
  14. Griffith, LM, et al. Improving cellular therapy for primary immune deficiency diseases: recognition, diagnosis, and management. J. Allergy Clin. Immunol. 2009; 124(6):1152-60.e12. PMID: 20004776

For management guidelines please refer to:

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ACD NM_001082486.1
ADA NM_000022.2
AK2 NM_001625.3
ATM NM_000051.3
B2M NM_004048.2
BCL10 NM_003921.4
CARD11 NM_032415.5
CD247 NM_198053.2
CD27 NM_001242.4
CD3D NM_000732.4
CD3E NM_000733.3
CD3G NM_000073.2
CD40LG NM_000074.2
CD8A NM_001768.6
CHD7 NM_017780.3
CIITA NM_000246.3
CORO1A* NM_007074.3
CTC1 NM_025099.5
CTPS1 NM_001905.3
DCLRE1B NM_022836.3
DCLRE1C NM_001033855.2
DKC1 NM_001363.4
DNMT3B NM_006892.3
DOCK2 NM_004946.2
DOCK8 NM_203447.3
EPG5 NM_020964.2
FOXN1 NM_003593.2
ICOS NM_012092.3
IKBKB NM_001556.2
IL21 NM_021803.3
IL21R NM_021798.3
IL2RG NM_000206.2
IL7R NM_002185.3
ITK NM_005546.3
JAK3 NM_000215.3
LCK NM_001042771.2
LIG4 NM_002312.3
LRBA NM_006726.4
MAGT1 NM_032121.5
MALT1 NM_006785.3
MAP3K14 NM_003954.4
NBN NM_002485.4
NFKBIA NM_020529.2
NHEJ1 NM_024782.2
NHP2 NM_017838.3
NOP10 NM_018648.3
ORAI1 NM_032790.3
PARN NM_002582.3
PGM3 NM_001199917.1
PMS2 NM_000535.5
PNP NM_000270.3
POLE NM_006231.3
PRKDC NM_006904.6
PTPRC NM_002838.4
RAC2 NM_002872.4
RAG1 NM_000448.2
RAG2 NM_000536.3
RFX5 NM_000449.3
RFXANK NM_003721.3
RFXAP NM_000538.3
RHOH NM_004310.4
RMRP NR_003051.3
RTEL1 NM_001283009.1
SEMA3E NM_012431.2
SH2D1A NM_002351.4
SMARCAL1 NM_014140.3
SP110 NM_004509.3
SPINK5 NM_006846.3
STAT3 NM_139276.2
STAT5B NM_012448.3
STIM1 NM_003156.3
STK4 NM_006282.3
TAP1 NM_000593.5
TAP2 NM_000544.3
TAPBP NM_003190.4
TBX1 NM_080647.1
TCN2 NM_000355.3
TERC NR_001566.1
TERT NM_198253.2
TINF2 NM_001099274.1
TNFRSF4 NM_003327.3
TTC7A NM_020458.3
WAS NM_000377.2
WIPF1 NM_001077269.1
ZAP70 NM_001079.3
ZBTB24 NM_014797.2

CORO1A: Deletion/duplication and sequencing analysis is not offered for exon 11 (NM_007074.3).

Clinical resources
Immunology gene list Invitae brochure
Patient resources
Patient guide: Genetic testing simplified
Test information
Forms page Specimen requirements page

References

  1. Allenspach, E, et al. X-Linked Severe Combined Immunodeficiency. 2003 Aug 26. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301584
  2. Baffelli, R, et al. Diagnosis, Treatment and Long-Term Follow Up of Patients with ADA Deficiency: a Single-Center Experience. J. Clin. Immunol. 2015; 35(7):624-37. PMID: 26376800
  3. Dvorak, CC, et al. Comparison of outcomes of hematopoietic stem cell transplantation without chemotherapy conditioning by using matched sibling and unrelated donors for treatment of severe combined immunodeficiency. J. Allergy Clin. Immunol. 2014; 134(4):935-943.e15. PMID: 25109802
  4. Griffith, LM, et al. Allogeneic hematopoietic cell transplantation for primary immune deficiency diseases: current status and critical needs. J. Allergy Clin. Immunol. 2008; 122(6):1087-96. PMID: 18992926
  5. Griffith, LM, et al. Improving cellular therapy for primary immune deficiency diseases: recognition, diagnosis, and management. J. Allergy Clin. Immunol. 2009; 124(6):1152-60.e12. PMID: 20004776
  6. Hershfield, M. Adenosine Deaminase Deficiency. 2006 Oct 03. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301656
  7. Kwan, A, et al. Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA. 2014; 312(7):729-38. PMID: 25138334
  8. Matthews, AG, et al. Compound heterozygous mutation of Rag1 leading to Omenn syndrome. PLoS ONE. 2015; 10(4):e0121489. PMID: 25849362
  9. Mäkitie, O, Kostjukovits, S. Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders. 2012 Mar 15. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 22420014
  10. Picard, C, et al. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J. Clin. Immunol. 2015; 35(8):696-726. PMID: 26482257
  11. Rosenberg, SL, Larkin, A. ZAP70-Related Severe Combined Immunodeficiency. 2009 Oct 20. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301777
  12. Shiow, LR, et al. Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2 deletion. Clin. Immunol. 2009; 131(1):24-30. PMID: 19097825
  13. Woodbine, L, et al. PRKDC mutations in a SCID patient with profound neurological abnormalities. J. Clin. Invest. 2013; 123(7):2969-80. PMID: 23722905
  14. de, la, Morena, MT, Nelson, RP. Recent advances in transplantation for primary immune deficiency diseases: a comprehensive review. Clin Rev Allergy Immunol. 2014; 46(2):131-44. PMID: 23832379

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