Ordering
  • Test code: 08132
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
Billing
 

Invitae T-B-NK+ Severe Combined Immunodeficiency (SCID) Panel

Test description

The Invitae T-B-NK+ Severe Combined Immunodeficiency (SCID) Panel analyzes 6 genes that are associated with T-B-NK+ severe combined immunodeficiency. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants provide accurate risk assessment and carrier status for at-risk relatives.

Order test

Primary panel (6 genes)

DCLRE1C LIG4 NHEJ1 PRKDC RAG1 RAG2

T-cell negative, B-cell negative, NK-cell positive severe combined immunodeficiency (SCID) including:



Gene Disorder Protein name Protein symbol
DCLRE1C DCLRE1C (Artemis) deficiency Artemis Artemis
LIG4 DNA ligase IV deficiency DNA ligase IV LIG4
NHEJ1 Cernunnos/XLF deficiency Cernunnos Cernunnos
PRKDC DNA PKcs deficiency DNA-PKcs DNA-PKcs
RAG1 RAG 1 deficiency recombinase activating gene 1 RAG1
RAG2 RAG 2 deficiency recombinase activating gene 2 RAG2

T-B-NK+ severe combined immunodeficiency (SCID) is an infantile-onset primary immunodeficiency that presents in blood with dysfunction of both T-cells and B-cells, while NK-cells levels remain normal, although non-functional. SCID is characterized by recurrent, overwhelming viral, bacterial and fungal infections and failure to thrive, which if untreated often lead to early death. Less severe mutations in SCID genes cause Omenn syndrome (with or without radiation sensitivity), a disorder characterized by infantile-onset generalized lymphopenia, hypogammaglobulinemia, histiocytosis, diffuse erythroderma/scleroderma, failure to thrive, recurrent infections, chronic diarrhea, lymphadenopathy, alopecia, hepatosplenomegaly, and hypereosinophilia, leading to early death. Features of the RAG-related SCIDs and Omenn syndrome can include the presence of granulomas in several organs like lungs, liver, spleen, lymph nodes, or skin. In DCLRE1C and NHEJ1-related SCID (or Omenn syndrome), patients also present with sensitivity to ionizing radiation (RS-SCID) due to a deficiency of DNA double strand break repair. In NHEJ1-related SCID, patients present, in addition, with microcephaly and growth retardation. In PRKDC-related SCID, additional features reported in some patients include autoimmunity, granulomas, growth failure, dysmorphia, seizures, and profoundly impaired neurological function. LIG4 syndrome is a highly variable disorder with a broad spectrum of severity. Patients can present in infancy with a range of manifestations from RS-SCID to combined immunodeficiency presenting in adolescence. Other features may include pancytopenia, microcephaly, short stature, developmental delay and characteristic facial features. In addition, patients have an increased risk for developing lymphomas and leukemias. However clinically asymptomatic patients with milder immunologic abnormalities and increased sensitivity to ionizing radiation have been reported.

Gene % of T-B-NK+ cases attributed
DCLRE1C ~18%
LIG4 rare
NHEJ1 rare
PRKDC rare
RAG1 ~72%
RAG2 ~9%

All causes of T-B-NK+ severe combined immunodeficiency are inherited in an autosomal recessive manner.

T-B-NK+ SCID accounts for approximately 21% of all cases of SCID. The estimated incidence of T-B-NK+ SCID in the US is 1:475,000, based upon data from universal newborn screening (NBS). RS-SCID is found with a very high incidence among Athabascan-speaking native American Indians with an incidence as high as 1 in 3,500 live births in Navajo populations.

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. Cirillo, E, et al. Severe combined immunodeficiency-an update. Ann. N. Y. Acad. Sci. 2015; 1356(1):90-106. PMID: 26235889
  2. Barth, RF, et al. Rapidly fatal familial histiocytosis associated with eosinophilia and primary immunological deficiency. Lancet. 1972; 2(7776):503-6. PMID: 4115568
  3. Ege, M, et al. Omenn syndrome due to ARTEMIS mutations. Blood. 2005; 105(11):4179-86. PMID: 15731174
  4. Corneo, B, et al. Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome. Blood. 2001; 97(9):2772-6. PMID: 11313270
  5. Villa, A, et al. Partial V(D)J recombination activity leads to Omenn syndrome. Cell. 1998; 93(5):885-96. PMID: 9630231
  6. Schuetz, C, et al. An immunodeficiency disease with RAG mutations and granulomas. N. Engl. J. Med. 2008; 358(19):2030-8. PMID: 18463379
  7. van, der, Burg, M, et al. A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining. J. Clin. Invest. 2009; 119(1):91-8. PMID: 19075392
  8. Woodbine, L, et al. PRKDC mutations in a SCID patient with profound neurological abnormalities. J. Clin. Invest. 2013; 123(7):2969-80. PMID: 23722905
  9. Mathieu, AL, et al. PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity. J. Allergy Clin. Immunol. 2015; 135(6):1578-88.e5. PMID: 25842288
  10. O'Driscoll, M, et al. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol. Cell. 2001; 8(6):1175-85. PMID: 11779494
  11. Ben-Omran, TI, et al. A patient with mutations in DNA Ligase IV: clinical features and overlap with Nijmegen breakage syndrome. Am. J. Med. Genet. A. 2005; 137A(3):283-7. PMID: 16088910
  12. Unal, S, et al. A novel mutation in a family with DNA ligase IV deficiency syndrome. Pediatr Blood Cancer. 2009; 53(3):482-4. PMID: 19418549
  13. Tamura, S, et al. Novel compound heterozygous DNA ligase IV mutations in an adolescent with a slowly-progressing radiosensitive-severe combined immunodeficiency. Clin. Immunol. 2015; 160(2):255-260. PMID: 26172957
  14. Felgentreff, K, et al. Ligase-4 Deficiency Causes Distinctive Immune Abnormalities in Asymptomatic Individuals. J. Clin. Immunol. 2016; 36(4):341-53. PMID: 27063650
  15. Riballo, E, et al. Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient. Curr. Biol. 1999; 9(13):699-702. PMID: 10395545
  16. Enders, A, et al. A severe form of human combined immunodeficiency due to mutations in DNA ligase IV. J. Immunol. 2006; 176(8):5060-8. PMID: 16585603
  17. Toita, N, et al. Epstein-Barr virus-associated B-cell lymphoma in a patient with DNA ligase IV (LIG4) syndrome. Am. J. Med. Genet. A. 2007; 143A(7):742-5. PMID: 17345618
  18. 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
  19. 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
  20. de, Villartay, JP. Congenital defects in V(D)J recombination. Br. Med. Bull. 2015; 114(1):157-67. PMID: 25987660
  21. American College of Medical Genetics. NBS ACT Sheet. Severe Combined Immunodeficiency (SCID) and Conditions Associated with T Cell Lymphopenia. https://www.acmg.net/StaticContent/ACT/SCID.pdf

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
DCLRE1C NM_001033855.2
LIG4 NM_002312.3
NHEJ1 NM_024782.2
PRKDC NM_006904.6
RAG1 NM_000448.2
RAG2 NM_000536.3