Invitae Severe Combined Immunodeficiency Panel


Test description

The Invitae Severe Combined Immunodeficiency Panel analyzes up to 19 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. 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 contact Client Services.

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Primary panel (18 genes)


Add-on CHARGE syndrome gene (1 gene)

Patients with CHARGE syndrome can have variable immune-system presentations, including mild to severe T-cell lymphopenia, abnormal T-cell function, and hypogammaglobulinemia (PMID: 26235889 ). Recent data from newborn screening laboratories have shown that some CHARGE patients can be identified through SCID newborn screening (PMID: 25138334 ). Given the immunological presentation overlap between SCID and CHARGE syndrome and the difficulty in differentiating between SCID and CHARGE syndrome on newborn screening assays, analyzing the CHD7 gene (associated with CHARGE syndrome) may be appropriate. This gene can be included at no additional charge.


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 76% 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.

Gene % of SCID cases attributed
ADA ~10%–15%
AK2 <1%
CD3D ~2%
CD3E unknown
IL2RG ~20%–28%
IL7R ~12%
JAK3 ~6%–7%
LIG4 unknown
NHEJ1 unknown
PNP unknown
PTPRC unknown
RAC2 unknown
RAG1 ~16%
RAG2 ~2%
RMRP <1%–4%
ZAP70 unknown

Many forms of SCID are autosomal recessive, though the most common cause of SCID is inherited in an X-linked manner. RAC2-associated neutrophil immunodeficiency syndrome is inherited in an autosomal dominant 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. 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. American College of Medical Genetics. NBS ACT Sheets and Algorithm Table. Accessed February 2016.
  3. 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
  4. 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
  5. 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
  6. 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
  7. Hershfield, M. Adenosine Deaminase Deficiency. 2006 Oct 03. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301656
  8. 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
  9. Matthews, AG, et al. Compound heterozygous mutation of Rag1 leading to Omenn syndrome. PLoS ONE. 2015; 10(4):e0121489. PMID: 25849362
  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. Müller, SM, et al. Transplacentally acquired maternal T lymphocytes in severe combined immunodeficiency: a study of 121 patients. Blood. 2001; 98(6):1847-51. PMID: 11535520
  12. 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
  13. Stephan, JL, et al. Severe combined immunodeficiency: a retrospective single-center study of clinical presentation and outcome in 117 patients. J. Pediatr. 1993; 123(4):564-72. PMID: 8410508
  14. Wahlstrom, J, et al. Transplacental maternal engraftment and posttransplantation graft-versus-host disease in children with severe combined immunodeficiency. J. Allergy Clin. Immunol. 2016; :None. PMID: 27444177
  15. 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

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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ADA NM_000022.2
AK2 NM_001625.3
CD247 NM_198053.2
CD3D NM_000732.4
CD3E NM_000733.3
CHD7 NM_017780.3
DCLRE1C NM_001033855.2
IL2RG NM_000206.2
IL7R NM_002185.3
JAK3 NM_000215.3
LIG4 NM_002312.3
NHEJ1 NM_024782.2
PNP NM_000270.3
PTPRC NM_002838.4
RAC2 NM_002872.4
RAG1 NM_000448.2
RAG2 NM_000536.3
RMRP NR_003051.3
ZAP70 NM_001079.3