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.
ADA AK2 CD247 CD3D CD3E CORO1A DCLRE1C IL2RG IL7R JAK3 LIG4 NHEJ1 PNP PRKDC PTPRC RAG1 RAG2 ZAP70
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.
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.
ADA AK2 CD247 CD3D CD3E CORO1A DCLRE1C IL2RG IL7R JAK3 LIG4 NHEJ1 PNP PRKDC PTPRC RAG1 RAG2 ZAP70
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
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
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:
For considerations for testing please refer to:
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).