Test Catalog

Test Id : SCDGP

Severe Combined Immunodeficiency Panel (63 genes), Next-Generation Sequencing, Varies

Useful For
Suggests clinical disorders or settings where the test may be helpful

Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of:

-Severe combined immunodeficiency (SCID)

-Combined immunodeficiency (CID)

-T-cell lymphopenia/deficiency

-Bare lymphocyte syndrome (BLS)

-Epstein-Barr virus-associated primary immunodeficiency disorder (EBV-associated PIDD)

 

Establishing a diagnosis and, in some cases, allowing for appropriate management and surveillance for disease features based on the gene involved

 

Identifying pathogenic variants within genes known to be associated SCID, CID, T-cell lymphopenia/deficiency, BLS, or EBV-associated PIDD allowing for predictive testing of at-risk family members

Genetics Test Information
Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test includes next-generation sequencing and supplemental Sanger sequencing to test for variants in the ADA(ADA1), ADA2 (CECR1), AK2, ATM, CD247(CD3Z), CD27, CD3D, CD3E, CD3G, CD8A, CHD7, CIITA, CORO1A, CTPS1, DCLRE1C(ARTEMIS), FOXN1, GATA2, IKBKB, IKBKG(NEMO), IL21, IL21R, IL2RG, IL7R, ITK, JAK3, LCK, LIG4, MAGT1, MALT1, MTHFD1, NFKBIA(IKBA), NHEJ1, ORAI1, PNP, PRKDC, PTPRC(CD45), RAC2, RAG1, RAG2, RBM8A, RFX5, RFXANK, RFXAP, RHOH, RMRP, SEMA3E, SH2D1A, SLC46A1, STAT5B, STIM1, STK4, TAP1, TAP2, TAPBP, TAZ, TBX1, TNFRSF4(OX40), TRAC, TTC7A,WAS, WIPF1, XIAP(BIRC4), ZAP70 genes.

 

This test uses Sanger sequencing to test for variants in certain exons of the following genes:

IKBKG (NEMO) Exons 3-10

CORO1A Exon 11

STAT5B Exons 6-8

 

Identification of a pathogenic variant may assist with prognosis, clinical management, familial screening, and genetic counseling.

Reflex Tests
Lists tests that may or may not be performed, at an additional charge, depending on the result and interpretation of the initial tests.

Test Id Reporting Name Available Separately Always Performed
FIBR Fibroblast Culture Yes No
CRYOB Cryopreserve for Biochem Studies No No

Testing Algorithm
Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

For skin biopsy or cultured fibroblast specimens, fibroblast culture and cryopreservation testing will be performed at an additional charge. If viable cells are not obtained, the client will be notified.

Special Instructions
Library of PDFs including pertinent information and forms related to the test

Method Name
A short description of the method used to perform the test

Custom Sequence Capture and Targeted Next-Generation Sequencing followed by Polymerase Chain Reaction (PCR) and Supplemental Sanger Sequencing

NY State Available
Indicates the status of NY State approval and if the test is orderable for NY State clients.

Yes

Reporting Name
Lists a shorter or abbreviated version of the Published Name for a test

SCID PID Gene Panel

Aliases
Lists additional common names for a test, as an aid in searching

ADA(ADA1)

ADA2 (CECR1)

AK2

Anhidrotic ectodermal dysplasia with immunodeficiency

ATM

Ataxia-telangiectasia and combined immunodeficiency

Bare lymphocyte syndrome

Barth syndrome

Cartilage-hair hypoplasia

CD247(CD3Z)

CD27

CD3D

CD3E

CD3G

CD8A

CHARGE syndrome

CHD7

CIITA

Combined immunodeficiency

CORO1A

CTPS1

DCLRE1C(ARTEMIS)

DiGeorge syndrome

Emberger syndrome

FOXN1

GATA2

IKBKB

IKBKG(NEMO)

IL21

IL21R

IL2RG

IL7R

Immunodeficiency with multilineage cytopenias

ITK

JAK3

LCK

LIG4

Lymphoproliferative syndrome 2

MAGT1

MALT1

MTHFD1

Neutrophil immunodeficiency syndrome

NFKBIA(IKBA)

NHEJ1

ORAI1

PNP

PRKDC

PTPRC(CD45)

RAC2

RAG1

RAG2

RBM8A

RFX5

RFXANK

RFXAP

RHOH

RMRP

SEMA3E

Severe combined immunodeficiency

SH2D1A

SLC46A1

STAT5B

STIM1

STK4

TAP1

TAP2

TAPBP

TAZ

TBX1

Thrombocytopenia-absent radius syndrome

TNFRSF4(OX40)

TRAC

TTC7A

WAS

WIPF1

Wiskott-Aldrich syndrome

X-linked lymphoproliferative syndrome

XIAP(BIRC4)

ZAP70

XMEN syndrome

Primary Immunodeficiency

Next Gen Sequencing Test

Testing Algorithm
Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

For skin biopsy or cultured fibroblast specimens, fibroblast culture and cryopreservation testing will be performed at an additional charge. If viable cells are not obtained, the client will be notified.

Specimen Type
Describes the specimen type validated for testing

Varies

Ordering Guidance

Necessary Information

1. Primary Immunodeficiencies Patient Information (T791) is strongly recommended, but not required, to be filled out and sent with the specimen. This information aids in providing a more thorough interpretation of test results. Ordering providers are strongly encouraged to complete the form and send it with the specimen.

2. Include physician name and phone number with specimen.

Specimen Required
Defines the optimal specimen required to perform the test and the preferred volume to complete testing

Patient Preparation: A previous bone marrow transplant from an allogenic donor or a recent (ie, <6 weeks from time of sample collection) heterologous blood transfusion will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

 

Submit only 1 of the following specimens:

 

Preferred:

Specimen Type: Whole blood

Container/Tube: Lavender top (EDTA)

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube. Do not aliquot.

Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated 14 days

 

Specimen Type: Blood spot

Supplies: Card-Blood Spot Collection Filter Paper (T493)

Container/Tube:

Preferred: Collection card (Whatman Protein Saver 903 Paper)

Acceptable: Whatman FTA Classic paper, Ahlstrom 226 filter paper, or Blood Spot Collection Card

Specimen Volume: 2 to 5 blood spots on collection card

Collection Instructions:

1. An alternative blood collection option for a patient older than1 year of age is finger stick.

2. Let blood dry on the filter paper at ambient temperature in a horizontal position for 3 hours.

3. Do not expose specimen to heat or direct sunlight.

4. Do not stack wet specimens.

5. Keep specimen dry.

Specimen Stability Information: Ambient (preferred)/Refrigerated

 

Specimen Type: Peripheral blood mononuclear cells (PBMC)

Container/Tube: Cell pellet

Collection Instructions: Send as a suspension in freezing medium or cell pellet frozen on dry ice.

Specimen Stability Information: Frozen

 

Specimen Type: Cultured fibroblasts

Container/Tube: T-75 or T-25 flask

Specimen Volume: 1 Full T-75 or 2 full T-25 flasks

Specimen Stability Information: Ambient (preferred)/Refrigerated <24 hours

Additional Information: Indicate the tests to be performed on the fibroblast culture cells. A separate culture charge will be assessed under FIBR / Fibroblast Culture. An additional 4 weeks is required to culture fibroblasts before genetic testing can occur.

 

Specimen Type: Skin biopsy

Supplies: Fibroblast Biopsy Transport Media (T115)

Container/Tube: Sterile container with any standard cell culture media (eg, minimal essential media, RPMI 1640). The solution should be supplemented with 1% penicillin and streptomycin. Tubes of culture media can be supplied upon request (Eagle's minimum essential medium with 1% penicillin and streptomycin).

Specimen Volume: 4-mm punch

Specimen Stability Information: Refrigerated (preferred)/Ambient

Additional Information: A separate culture charge will be assessed under FIBR / Fibroblast Culture. An additional 4 weeks is required to culture fibroblasts before genetic testing can occur.

 

Specimen Type: Extracted DNA

Container/Tube: 2 mL screw top tube

Specimen Volume: 100 mcL (microliters)

Collection Instructions:

1. The preferred volume is 100 mcL at a concentration of 250 ng/mcL

2. Include concentration and volume on tube.

Specimen Stability Information: Frozen (preferred)/Ambient/Refrigerated

Special Instructions
Library of PDFs including pertinent information and forms related to the test

Forms

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. Primary Immunodeficiencies Patient Information (T791) is recommended. See Special Instructions.

Specimen Minimum Volume
Defines the amount of sample necessary to provide a clinically relevant result as determined by the Testing Laboratory

Whole blood: 1 mL

Reject Due To
Identifies specimen types and conditions that may cause the specimen to be rejected

  All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.

Specimen Stability Information
Provides a description of the temperatures required to transport a specimen to the performing laboratory, alternate acceptable temperatures are also included

Specimen Type Temperature Time Special Container
Varies Varies (preferred)

Useful For
Suggests clinical disorders or settings where the test may be helpful

Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of:

-Severe combined immunodeficiency (SCID)

-Combined immunodeficiency (CID)

-T-cell lymphopenia/deficiency

-Bare lymphocyte syndrome (BLS)

-Epstein-Barr virus-associated primary immunodeficiency disorder (EBV-associated PIDD)

 

Establishing a diagnosis and, in some cases, allowing for appropriate management and surveillance for disease features based on the gene involved

 

Identifying pathogenic variants within genes known to be associated SCID, CID, T-cell lymphopenia/deficiency, BLS, or EBV-associated PIDD allowing for predictive testing of at-risk family members

Genetics Test Information
Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test includes next-generation sequencing and supplemental Sanger sequencing to test for variants in the ADA(ADA1), ADA2 (CECR1), AK2, ATM, CD247(CD3Z), CD27, CD3D, CD3E, CD3G, CD8A, CHD7, CIITA, CORO1A, CTPS1, DCLRE1C(ARTEMIS), FOXN1, GATA2, IKBKB, IKBKG(NEMO), IL21, IL21R, IL2RG, IL7R, ITK, JAK3, LCK, LIG4, MAGT1, MALT1, MTHFD1, NFKBIA(IKBA), NHEJ1, ORAI1, PNP, PRKDC, PTPRC(CD45), RAC2, RAG1, RAG2, RBM8A, RFX5, RFXANK, RFXAP, RHOH, RMRP, SEMA3E, SH2D1A, SLC46A1, STAT5B, STIM1, STK4, TAP1, TAP2, TAPBP, TAZ, TBX1, TNFRSF4(OX40), TRAC, TTC7A,WAS, WIPF1, XIAP(BIRC4), ZAP70 genes.

 

This test uses Sanger sequencing to test for variants in certain exons of the following genes:

IKBKG (NEMO) Exons 3-10

CORO1A Exon 11

STAT5B Exons 6-8

 

Identification of a pathogenic variant may assist with prognosis, clinical management, familial screening, and genetic counseling.

Testing Algorithm
Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

For skin biopsy or cultured fibroblast specimens, fibroblast culture and cryopreservation testing will be performed at an additional charge. If viable cells are not obtained, the client will be notified.

Clinical Information
Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Severe combined immunodeficiency (SCID) is characterized by the absence or dysfunction of T lymphocytes, which affects both cellular and humoral adaptive immunity resulting in a severe form of this inherited primary immunodeficiency disorder that may be life-threatening. In classic form, SCID presents in infancy with persistent respiratory and gastrointestinal infections, failure to thrive, or graft-versus-host disease (due to engraftment of maternal T cells). The absence of lymphoid tissue, immunoglobulins, and T lymphocytes may also be noted. Typically, patients will have less than 300 autologous CD3 T cells/mcL blood and will require immediate medical intervention.

 

Atypical or "leaky" SCID tends to present later (ie, over 12 months of age) with recurrent, severe, and prolonged viral infections, bronchiectasis, autoimmune manifestations including cytopenias, and failure to thrive. Patients may display partial or restricted antigen-specific antibody responses. Leaky SCID is also related to hypomorphic variants in genes normally associated with classic SCID, as indicated above.

 

Omenn syndrome, a form of leaky SCID that typically presents in infancy, is characterized by erythroderma, alopecia, hepatosplenomegaly, and lymphadenopathy. Laboratory findings may include elevated IgE, eosinophilia, and lymphocytosis. Omenn syndrome is due to genetic variants in at least 7 different genes that allow for partial activity, although disease severity is likely only partially attributable to genotype. While RAG1 and RAG2 hypomorphic variants are most often associated with leaky SCID or Omenn syndrome, patients may have variants affecting other genes/proteins, such as Artemis or interleukin-7 receptor (IL-7R) alpha. There may be forms of leaky SCID with hypomorphic variants in these genes that do not have the associated Omenn syndrome phenotype.

 

SCID can be classified as T-B+ or T-B- SCID, with further subdivision possible based on the presence or absence of NK cells. T-B+ SCID, characterized by impaired development of mature T-cells along with present but non-functional B-cells, is most often caused by genetic variants that affect cytokine-mediated signaling. X-linked SCID is due to mutations in the IL2RG gene, which encodes the common gamma chain that is a part of the IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors. Autosomal recessive forms due to variants in JAK3 or IL7R also disrupt cytokine signaling. Genetic variants in one of the four CD3 genes (CD3G, CD3D, CD3E, and CD247[CD3Z]) inhibit CD3 signaling and also cause T-B+ SCID. T-B+ SCID may also be due to coronin-1A deficiency causing disruption of thymic egress of T cells and defective T cell locomotion, or due to CD45 deficiency (caused by variants in PTPRC). Patients with coronin-1A deficiency may also have other syndromic manifestations.

 

T-B- SCID is typically characterized by a defect in V(D)J recombination. V(D)J recombination begins with proteins encoded by RAG1 and RAG2 forming a heterodimer and making a single-stranded nick and forming hairpin structured ends between a coding element (V, D, or J segment) and the recombination signal sequence. Then, in the processing phase, the DNA-protein kinase complex (including a protein encoded by PRKDC) binds to and opens the hairpin structure by phosphorylating Artemis (encoded by DCLRE1C). Prior to ligation of the open ends by LIG4/XRCC4 and Cernunnos/XLF (encoded by NHEJ1), additional editing takes place. Adenosine deaminase deficiency, which results in accumulation of metabolic by-products that are toxic to lymphocytes, and results in T-B- and NK- SCID. It accounts for approximately 15% of cases and is inherited as an autosomal recessive condition, which may include neurological problems (ie, cognitive impairment, hearing/visual impairment, and movement disorders) in addition to SCID. Reticular dysgenesis, due to genetic variants in AK2, is the most severe form of combined immunodeficiency and is characterized by congenital agranulocytosis, lymphopenia, lymphoid and thymic hypoplasia, along with bilateral sensorineural deafness.

 

Subsets of T cells may be decreased due to genetic variants in certain genes, without an appreciable effect on other T cell subsets. For example, genetic variants in CD8A, ZAP70, TAP1, TAP2, or TAPBP can result in absent or reduced CD8+ T cells in the presence of normal quantity of CD4+ T cells. In contrast, genetic variants in CIITA, RFXANK, RFX5, or RFXAP result in absent or reduced CD4+ T cells. These genes are associated with bare lymphocyte syndromes types 1 and 2 respectively, or major histocompatibility complex (MHC) class I and II deficiencies. In addition, variants in ITK, MAGT1, RHOH, STK4, TRAC, LCK, MALT1, IL21, IL21R, TNFRSR4 (OX40), IKBKB, CD27, or CTPS1 are thought to generally result in combined immunodeficiency that is generally less clinically profound than SCID.

 

Several combined immunodeficiencies are associated other features and syndromes. Variants in WAS and WIPF1 present with combined immunodeficiency and congenital thrombocytopenia, while variants in RBM8A are associated with thrombocytopenia-absent radius syndrome. DNA repair defects are commonly observed along with combined immunodeficiency in ataxia-telangiectasia (due to variants in ATM). Thymic defects with additional congenital anomalies may be observed in DiGeorge syndrome (represented on this panel by TBX1), CHARGE syndrome (due to variants in CHD7 or SEMA3E), and patients with genetic variants in FOXN1. Immune-osseous dysplasias along with combined immunodeficiency may be observed in cartilage hair hypoplasia (due to variants in RMRP), while those with variants in STAT5B may have growth hormone insensitivity. Combined immunodeficiency (CID) along with defects of vitamin B12 and folate metabolism may be observed in patients with genetic variants in SLC46A1 or MTHFD1. Anhidrotic ectodermal dysplasia with immunodeficiency results from genetic variants in IKBKG (NEMO) or NFKBIA (IKBA). Calcium channel defects are an associated feature in those with variants in ORAI1 or STIM1. In addition to CID, patients with variants in TTC7A may have multiple intestinal atresias. Barth syndrome along with combined immunodeficiency can be observed in patients with variants in TAZ. Some of these defects can be identified by newborn screening (NBS) for SCID, while others do not present with severe enough T cell lymphopenia in the neonatal period to be identified by NBS.

 

Table. Genes included in this test

  

Gene (alias)

Protein

OMIM

Incidence

 Inheritance

Phenotype disorder

ADA (ADA1)

Adenosine deaminase

608958

1-9 per million live births

AR, partial ADA deficiency may lead to delayed or milder presentation

SCID (T-B-, Ig-, NK-)

ADA2 (CECR1)

Adenosine deaminase CECR1 isoform a precursor

607575

 

 AR

SCID (T-B-, Ig-, NK-) Sneddon syndrome, polyarteritis nodosa, childhood-onset, early-onset stroke, vasculopathy, B cell immunodeficiency, neutrophil and macrophage polarization defects

AK2

Adenylate kinase 2, mitochondrial isoform a

103020

 

AR

SCID (T-, B-/normal, Ig- with granulocytopenia, deafness), reticular dysgenesis

ATM

Serine-protein kinase ATM

607585

1/40,000-100,000

AR

Ataxia-telangiectasia and combined immunodeficiency (T with abnormal proliferation to mitogens, B+, Ig often decreased [particularly IgA, IgE, and IgG with increased IgM monomers])

CD247 (CD3Z)

T-cell surface glycoprotein CD3 zeta chain isoform 1 precursor

186780

 

AR

SCID (T- B(normal), Ig- NK normal, no gamma/delta T cells

CD27

CD27 antigen precursor

186711

 

AR

Combined immunodeficiency (T+ B no memory, Ig hypogamma-globulinemia following EBV), lymphoproliferative syndrome 2

CD3D

T-cell surface glycoprotein CD3 delta chain isoform A precursor

186790

 

AR

SCID (T-B+, Ig-, NK+, no gamma/delta T cells)

CD3E

T-cell surface glycoprotein CD3 epsilon chain precursor

186830

 

AR

SCID (T-B+, Ig-, NK+, no gamma/delta T cells)

CD3G

T-cell surface glycoprotein CD3 gamma chain precursor

186740

 

AR

Combined immunodeficiency (T-normal with reduced TCR expression, B+ Ig+)

CD8A

T-cell surface glycoprotein CD8 alpha chain isoform 1 precursor

186910

 

AR

CD8 deficiency (normal CD4 cells, B+, Ig+)

CHD7

Chromodomain-helicase-DNA-binding protein 7 isoform 1

608892

 

AD

Combined immunodeficiency (T decreased/normal [response to PHA may be decreased], B+, Ig decreased/normal), CHARGE syndrome

CIITA

MHC class II transactivator isoform 2

600005

 

AR

Combined immunodeficiency (decreased CD4 cells and absent MHC II expression on lymphocytes, B+, Ig decreased/normal)

CORO1A

Coronin-1A

605000

 

AR

SCID (T-B+, Ig-, with detectable thymus EBV-associated B-cell lymphoproliferation), CGD

CTPS1

CTP synthase 1 isoform a

123860

 

AR

Combined immunodeficiency (T decreased/normal with decreased/normal proliferation, B decreased/ normal, Ig high/normal)

DCLRE1C (ARTEMIS)

Protein Artemis isoform a

605988

1/2,000 in Athabaskan-speaking populations

AR

SCID (T-B-, Ig- with radiation sensitivity), omenn syndrome

FOXN1

Forkhead box protein N1

 600838

 

AR

Combined immunodeficiency (T markedly decreased, B+, Ig decreased) congenital alopecia, and nail dystrophy, nude SCID

GATA2

Endothelial transcription factor GATA-2 isoform 1

137295

 

AD

Immunodeficiency with multilineage cytopenias, emberger syndrome, susceptibility to acute myeloid Leukemia and myelodysplastic syndrome

IKBKB

Inhibitor of nuclear factor kappa-B kinase subunit beta isoform 1

 603258

Rare

AR

Combined immunodeficiency (T normal total with absent regulatory and gamma-delta, B normal [impaired BCR activation], Ig decreased)

IKBKG (NEMO)

NF-kappa-B essential modulator isoform a

300248

Rare

XL

Combined immunodeficiency (T decreased/normal with poor activation, B normal [low memory B cells], Ig decreased with poor specific antibody responses), anhidrotic ectodermal dysplasia, mycobacterial susceptibility

IL21

Interleukin-21 isoform 1 precursor

605384

 

AR

Immunodeficiency (T normal number but low function, B low, IgG deficiency), severe early onset colitis

IL21R

Interleukin-21 receptor isoform 1 precursor

605383 

 

AR/AD

Immunodeficiency (abnormal T cell cytokine production and abnormal proliferation to specific stimuli, B normal, Ig normal but impaired specific responses), elevated IgE (autosomal dominant)

IL2RG

Cytokine receptor common subunit gamma precursor

308380

Approximately 1/50,000-100,000 live births

XL

SCID (T-, B+(normal to increased), Ig-, NK-)

IL7R

IL7R

146661

 

AR

SCID (T- B+, Ig decreased, NK+), omenn syndrome

ITK

Tyrosine-protein kinase ITK/TSK

186973 

Rare

AR

Immunodeficiency (progressive T cell disease with normal B cells and normal/decreased Ig), lymphoproliferative syndrome 1, EBV susceptibility

JAK3

Tyrosine-protein kinase JAK3

600173

1/500,000 live births

AR

SCID (T-B+, Ig-, NK-)

LCK

Tyrosine-protein kinase LCK

153390

 

AR

Immunodeficiency (T normal total numbers but CD4 lymphopenia, low Treg, restricted T repertoire and impaired TCR signaling; B normal, Ig: normal IgG and IgA with increased IgM)

LIG4

DNA ligase 4

601837

 

AR

SCID (T-B- Ig-, NK+ with radiation sensitivity, microcephaly, and developmental defects), omenn syndrome, dubowitz syndrome

MAGT1

Magnesium transporter protein 1

300715

 

XL

Combined immunodeficiency (T decreased CD4 and impaired proliferation in response to CD3, B+ Ig+), EBV susceptibility

MALT1

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 isoform a

604860

 

AR

Immunodeficiency (T normal but with impaired proliferation; B+, Ig normal with impaired antibody response)

MTHFD1

C-1-tetrahydrofolate synthase, cytoplasmic

172460

 

AR

Combined immunodeficiency related to folate deficiency (T low, B low, Ig decreased); megaloblastic anemia

NFKBIA (IKBA)

NF-kappa-B inhibitor alpha

164008

Rare

AD

Anhidrotic ectodermal dysplasia with immunodeficiency (T normal number with impaired TCR activation, B normal number with impaired BCR activation, Ig decreased with poor specific antibody responses)

NHEJ1 (Cernunnos/XLF)

Non-homologous end-joining factor 1

611290

 

 

SCID (T-B- Ig- with microcephaly and growth retardation, sensitivity to ionizing radiation)

ORAI1

Calcium release-activated calcium channel protein 1

610277

 

AR

Immunodeficiency (T normal with defected TCR activation, B normal, Ig normal)

PNP

Purine nucleoside phosphorylase

164050

 

AR

CID (T-, B+, Ig low/normal), PNP deficiency, neurological deficits

PRKDC

DNA-dependent protein kinase catalytic subunit isoform 1 (DNA-PKcs)

600899

 

AR

SCID (T-B-, Ig- with radiation sensitivity, microcephaly, and developmental defects)

PTPRC (CD45)

Receptor-type tyrosine-protein phosphatase C isoform 1 precursor

151460

Unknown

AR

SCID (T-B+ Ig- normal gamma/delta T cells, NK+)

RAC2

Ras-Related C3 botulinum toxin substrate 2

602049

 

AD (in progress)

Neutrophil immunodeficiency syndrome; identified with T cell lymphopenia in NBS SCID; may affect T cell numbers and/or function

RAG1

V(D)J recombination-activating protein 1

179615

Approximately 1/100,000 live births

AR

SCID (T-B-, Ig-, NK+), omenn syndrome

RAG2

V(D)J recombination-activating protein 2

179616

Approximately 1/100,000 live births

AR

SCID (T-B-, Ig-, NK+), omenn syndrome

RBM8A

RNA-binding protein 8A

605313

 

AR

Thrombocytopenia-absent radius syndrome

RFX5

DNA-binding protein RFX5

601863

 

AR

Bare lymphocyte syndrome (decreased CD4 cells and absent MHC II expression on lymphocytes, B+, Ig+/decreased)

RFXANK

DNA-binding protein RFXANK isoform a

603200

 

AR

Bare lymphocyte syndrome (decreased CD4 cells and absent MHC II expression on lymphocytes, B+, Ig+/decreased)

RFXAP

Regulatory factor X-associated protein

601861

 

AR

Bare lymphocyte syndrome (decreased CD4 cells and absent MHC II expression on lymphocytes, B+, Ig+/decreased)

RHOH

Rho-related GTP-binding protein RhoH precursor

602037

 

AR

Combined immunodeficiency (T normal but low naive T cells, restricted repertoire, and impaired proliferation in response to CD3; B+, Ig+)

RMRP

RNA component of mitochondrial RNA processing endoribonuclease

157660

 

AR

Cartilage-hair hypoplasia, SCID (T severely decreased to normal with impaired proliferation; B_, Ig normal or reduced); Omenn syndrome

SEMA3E

Semaphorin-3E isoform 1 precursor

608166

 

AD

CHARGE syndrome; Combined immunodeficiency (T decreased/normal [response to PHA may be decreased], B+, Ig decreased/normal)

SH2D1A

SH2 domain-containing protein 1A isoform 1

300490

1/million males

XL

X-linked lymphoproliferative syndrome (normal/increased activated T cells, reduced memory B cells, partially defective NK cell and CTL cytotoxic activity)

SLC46A1

Proton-coupled folate transporter isoform 1

611672

 

AR

Combined immunodeficiency related to folate deficiency (T variable, B variable, Ig decreased); megaloblastic anemia

STAT5B

Signal transducer and activator of transcription 5B

604260

Rare

AR

Immunodeficiency (T modestly decreased, B+, Ig+) with growth hormone insensitivity

STIM1

Stromal interaction molecule 1 isoform 2 precursor

605921

 

AR/AD

Immunodeficiency (T normal with defective TCR mediated activation, B+, Ig+)(AR)

STK4

SERINE/THREONINE PROTEIN KINASE 4

614868

 

AR

Combined immunodeficiency (T: altered proportion of terminal differentiated effector memory cells with restricted repertoire, low naive T cells, impaired proliferation; B decreased, Ig high)

TAP1

Antigen peptide transporter 1 isoform 1

170260

 

AR

Bare lymphocyte syndrome (decreased CD8 with absent MHC I expression on lymphocytes, normal B cells, normal Ig) with vasculitis

TAP2

Antigen peptide transporter 2 isoform 2

170261

 

AR

Bare lymphocyte syndrome (decreased CD8 with absent MHC I expression on lymphocytes, normal B cells, normal Ig) with vasculitis

TAPBP

Tapasin isoform 1 precursor

601962

 

AR

Bare lymphocyte syndrome (decreased CD8 with absent MHC I expression on lymphocytes, normal B cells, normal Ig) with vasculitis

TAZ

Tafazzin isoform 1

300394

 

XL

Barth syndrome

TBX1

T-box transcription factor TBX1 isoform C

602054

 

AD

DiGeorge syndrome with immunodeficiency (T decreased or normal, B normal, Ig normal or decreased)

TNFRSF4 (OX40)

Tumor necrosis factor receptor superfamily member 4 precursor

600315

 

AR

Immunodeficiency (normal T cell numbers with decreased antigen specific memory CD4; normal B cell numbers with reduced memory B cells; normal Ig)

TRAC

T cell receptor alpha constant

186880

 

AR

Immunodeficiency (TCR-alpha/beta deficiency and impaired T cell proliferation; B+, Ig+)

TTC7A

Tetratricopeptide repeat protein 7A isoform 2

609332

 

AR

Immunodeficiency with multiple intestinal atresias (T variable/ absent, B+, Ig decreased)

WAS

Wiskott-Aldrich syndrome protein

300392

 

XL, GOF

Wiskott-Aldrich syndrome (progressive disease with abnormal lymphocyte responses to anti-CD3, B+, Ig: decreased IgM, decreased antibody responses to polysaccharides, often increased IgA and IgE)

WIPF1

WAS/WASL-interacting protein family member 1

602357

 

AR

Wiskott-Aldrich syndrome (reduced/defective lymphocyte responses to anti-CD3; B low; Ig normal except increased IgE)

XIAP (BIRC4)

E3 ubiquitin-protein ligase XIAP

300079

1/million males

XL

X-linked lymphoproliferative syndrome (increased T cell susceptibility to apoptosis to CD95 and enhanced activation-induced cell death)

ZAP70

Tyrosine-protein kinase ZAP-70 isoform 1

176947

 

AR

Selective

 

ADA=adenosine deaminase

AD=autosomal dominant

AR=autosomal recessive

GOF=gain of function

MHC=major histocompatibility complex

XL=X-linked

Reference Values
Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation
Provides information to assist in interpretation of the test results

Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics (ACMG) recommendations as a guideline. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

 

Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.

Cautions
Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Clinical Correlations:

Some individuals who have involvement of one or more of the genes on the panel may have a variant that is not identified by the methods performed (eg, promoter variants, deep intronic variants). The absence of a variant, therefore, does not eliminate the possibility of disease. Test results should be interpreted in context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

 

For predictive testing of asymptomatic individuals, it is often useful to first test an affected family member. Identification of a pathogenic variant in an affected individual allows for more informative testing of at-risk individuals.

 

Technical Limitations:

Next-generation sequencing may not detect all types of genetic variants. The variant detection software has lower detection efficiency for insertion/deletion variants as compared to single nucleotide variants. Therefore, small deletions and insertions greater than 8 nucleotides in length may not be detected by this test. Copy number variations (CNV) are not currently reported for any of the genes on this panel. Additionally, rare alterations (ie, polymorphisms) may be present that could lead to false-negative or false-positive results. In some cases, DNA variants of undetermined significance may be identified. If results do not match clinical findings, consider alternative methods for analyzing these genes, such as Sanger sequencing or large deletion/duplication analysis. If the patient has had an allogeneic blood or bone marrow transplant or a recent (ie, <6 weeks from time of sample collection) heterologous blood transfusion, results may be inaccurate due to the presence of donor DNA. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

 

Reclassification of Variants Policy:

At this time, it is not standard practice for the laboratory to systematically review likely deleterious alterations or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time. Consultation with a healthcare provider, or team of healthcare providers, with expertise in genetics and primary immunodeficiencies, is recommended for interpretation of this result.

 

A list of benign and likely benign variants detected is available from the lab upon request.

 

Contact the laboratory if additional information is required regarding the transcript or human genome assembly used for the analysis of results.

Clinical Reference
Recommendations for in-depth reading of a clinical nature

1. Picard C, Gaspar HB, Al-Herz W, et al: International Union of Immunological Societies: 2017 Primary Immunodeficiency Disease Committee report on inborn errors of immunity. J Clin Immunol. 2018;38:96-128. doi: 10.1007/s10875-017-0464-9

2. Shearer WT, Dunn E, Notarangelo LD, et al: Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn Syndrome: The Primary Immune Deficiency Treatment Consortium Experience. J Allergy Clin Immunol. April 2014;133(4):1092-1098. doi: 10.1016/j.jaci.2013.09.044

3. Bousfiha AA, Jeddane L, Ailal F, et al: A phenotypic approach for IUIS PID classification and diagnosis: Guidelines for clinicians at the bedside. J Clin Immunol. 2013;33:1078-1087

4. Raje N, Soden S, Swanson D, Kingsmore SF, Dinwiddie DL: Utility of next generation sequencing in clinical primary immunodeficiencies. Curr Allergy Asthma Rep. 2014;14:468

5. Taylor GS, Long HM, Brooks JM, Rickinson AB, Hislop AD: The immunology of Epstein-Barr virus-induced disease. Annu Rev Immunol. 2015;33:787-821. doi: 10.1146/annurev-immunol-032414-112326

6. DeSandro A, Nagarajan UM, Boss JM: The bare lymphocyte syndrome: Molecular clues to the transcriptional regulation of major histocompatability complex class II genes. Am J Hum Genet. 1999;65:279-286. doi: 10.1086/302519

7. Walkovich K, Vander Lugt M: ZAP70-related combined immunodeficiency. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2009. Updated June 8, 2017. Accessed November 27, 2017. Available at www.ncbi.nlm.nih.gov/books/NBK20221/

8. Hershfield M: Adenosine deaminase deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2006 Updated March 16, 2017 Mar 16. Accessed  November 27, 2017. Available at www.ncbi.nlm.nih.gov/books/NBK1483/

9. Allenspach E, Rawlings DJ, Scharenberg AM: X-linked severe combined immunodeficiency. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews [Internet[. University of Washington, Seattle; 2003 Updated April 14, 2016. Accessed November 27, 2017. Available at www.ncbi.nlm.nih.gov/books/NBK1410/

10. Crequer A, Picard C, Patin E, et al: Inherited MST1 deficiency underlies susceptibility to EV-HPV infections. PLoS One. 2012;7(8):e44010

11. Kwan A, Abraham RS, Currier R, et al: Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA. 2014;312:729-738. doi: 10.1001/jama.2014.9132

Special Instructions
Library of PDFs including pertinent information and forms related to the test

Method Description
Describes how the test is performed and provides a method-specific reference

Next-generation sequencing (NGS) is performed using an Illumina instrument with paired-end reads. The DNA is prepared for NGS using a custom Agilent SureSelect Target Enrichment System. Data is analyzed with a bioinformatics software pipeline. Supplemental Sanger sequencing is performed in select regions including CORO1A (exon 11), IKBKG (exons 3-10), and STAT5B (exons 6-8). Additional Supplemental Sanger sequencing may be performed occasionally in regions where NGS is insufficient for data capture or not specific enough to correctly identify a variant.(Unpublished Mayo method)

 

Genes analyzed: ADA(ADA1), ADA2 (CECR1), AK2, ATM, CD247(CD3Z), CD27, CD3D, CD3E, CD3G, CD8A, CHD7, CIITA, CORO1A, CTPS1, DCLRE1C(ARTEMIS), FOXN1, GATA2, IKBKB, IKBKG(NEMO), IL21, IL21R, IL2RG, IL7R, ITK, JAK3, LCK, LIG4, MAGT1, MALT1, MTHFD1, NFKBIA(IKBA), NHEJ1, ORAI1, PNP, PRKDC, PTPRC(CD45), RAC2, RAG1, RAG2, RBM8A, RFX5, RFXANK, RFXAP, RHOH, RMRP, SEMA3E, SH2D1A, SLC46A1, STAT5B, STIM1, STK4, TAP1, TAP2, TAPBP, TAZ, TBX1, TNFRSF4(OX40), TRAC, TTC7A, WAS, WIPF1, XIAP(BIRC4), ZAP70

PDF Report
Indicates whether the report includes an additional document with charts, images or other enriched information

No

Day(s) Performed
Outlines the days the test is performed. This field reflects the day that the sample must be in the testing laboratory to begin the testing process and includes any specimen preparation and processing time before the test is performed. Some tests are listed as continuously performed, which means that assays are performed multiple times during the day.

Monday

Report Available
The interval of time (receipt of sample at Mayo Clinic Laboratories to results available) taking into account standard setup days and weekends. The first day is the time that it typically takes for a result to be available. The last day is the time it might take, accounting for any necessary repeated testing.

2 to 8 weeks

Specimen Retention Time
Outlines the length of time after testing that a specimen is kept in the laboratory before it is discarded

Extracted DNA: 2 months

Performing Laboratory Location
Indicates the location of the laboratory that performs the test

Rochester

Fees
Several factors determine the fee charged to perform a test. Contact your U.S. or International Regional Manager for information about establishing a fee schedule or to learn more about resources to optimize test selection.

  • Authorized users can sign in to Test Prices for detailed fee information.
  • Clients without access to Test Prices can contact Customer Service 24 hours a day, seven days a week.
  • Prospective clients should contact their Regional Manager. For assistance, contact Customer Service.

Test Classification
Provides information regarding the medical device classification for laboratory test kits and reagents. Tests may be classified as cleared or approved by the US Food and Drug Administration (FDA) and used per manufacturer instructions, or as products that do not undergo full FDA review and approval, and are then labeled as an Analyte Specific Reagent (ASR) product.

This test was developed, and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the US Food and Drug Administration.

CPT Code Information
Provides guidance in determining the appropriate Current Procedural Terminology (CPT) code(s) information for each test or profile. The listed CPT codes reflect Mayo Clinic Laboratories interpretation of CPT coding requirements. It is the responsibility of each laboratory to determine correct CPT codes to use for billing.

CPT codes are provided by the performing laboratory.

81443

Test Setup Resources

Setup Files
Test setup information contains test file definition details to support order and result interfacing between Mayo Clinic Laboratories and your Laboratory Information System.

Excel | Pdf

Sample Reports
Normal and Abnormal sample reports are provided as references for report appearance.

Normal Reports | Abnormal Reports

SI Sample Reports
International System (SI) of Unit reports are provided for a limited number of tests. These reports are intended for international account use and are only available through MayoLINK accounts that have been defined to receive them.

SI Normal Reports | SI Abnormal Reports