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  1. Test Catalog
  2. Invitae Autoimmune Lymphoproliferative Disorders (ALPS) Panel

Invitae Autoimmune Lymphoproliferative Disorders (ALPS) Panel

Test description

This test analyzes up to 11 genes that are associated with a hereditary predisposition to the development of autoimmune lymphoproliferative syndrome (ALPS) and ALPS-like disorders. These genes were selected based on the available evidence to date to provide Invitae’s most comprehensive hereditary ALPS panel.

Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations.

If the patient has undergone a bone marrow transplant prior to genetic testing or currently has a hematological malignancy with actively circulating tumor cells, testing a sample type not derived from blood (such as skin biopsy) is warranted. While we do not accept this sample type directly, we can accept gDNA derived from skin or muscle, though deletion/duplication analysis is not guaranteed for gDNA samples because the success rate varies based on sample quality. Please see our Specimen Requirements for more details.

Genes tested

Primary panel

CASP8 CTLA4 FAS FASLG ITK MAGT1 PIK3CD PRKCD STAT3

Add-on Preliminary-evidence Genes for Autoimmune Lymphoproliferative Disorders (ALPS)

CASP10 FADD

In addition to the primary panel, clinicians can also choose to include 2 genes that have preliminary evidence of association with ALPS. At this time, the association of these genes with ALPS remains uncertain, but some clinicians may wish to include genes that may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.

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Primary panel (9 genes)

CASP8 CTLA4 FAS FASLG ITK MAGT1 PIK3CD PRKCD STAT3

Panel details and technical assay limitations
Add-on Preliminary-evidence Genes for Autoimmune Lymphoproliferative Disorders (ALPS) (2 genes)

In addition to the primary panel, clinicians can also choose to include 2 genes that have preliminary evidence of association with ALPS. At this time, the association of these genes with ALPS remains uncertain, but some clinicians may wish to include genes that may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.

CASP10 FADD

Panel details and technical assay limitations

Clinical information



Gene Disorder Protein name Protein symbol
CASP8 ALPS IIb, caspase 8 deficiency caspase-8 CASP8
CTLA4 CTLA4 deficiency (ALPSV) Cytotoxic T Lymphocyte antigen 4 CTLA4
FAS ALPS-FAS FAS antigen FAS; CD95
FASLG ALPS-FASLG FAS ligand; CD95 ligand FASLG
ITK lymphoproliferative syndrome type 1 (LPFS1) interleukin 2 inducible T-cell kinase ITK
MAGT1 X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN) magnesium transporter 1 MAGT1
PIK3CD Activated PI3K-δ p110-delta protein p110-delta
PRKCD PRKC delta deficiency protein kinase C delta PRKCD
STAT3 AD-HIES (Job or Buckley Syndrome), STAT3 GOF mutations signal transducer and activator of transcription 3 STAT3

ALPS is a rare immune system disorder, typically presenting in childhood. Lymphoproliferation, including lymphadenopathy, hypersplenia, and hepatomegaly, is the most common symptom, however these can lessen with age. Roughly 70% of individuals diagnosed with ALPS also have autoimmunity, including multilineage cytopenia, that may persist with age. Less frequently, other organ systems, such as kidney, gut, eye, liver and joints, may also develop autoimmune symptoms. Ten to twenty percent of Individuals with ALPS develop cancer, most commonly lymphoma. Most individuals diagnosed with ALPS do not have an increased risk for infections, however immunosuppressant medications commonly used to treat ALPS do increase infection risk. Penetrance for ALPS-related symptoms can vary depending on which gene is found to have a pathogenic variant.

Determination of an underlying genetic predisposition in an individual with a personal or family history of ALPS is critical for the selection of therapy regimens, consideration of bone marrow or stem cell transplant, long-term cancer surveillance and prognosis, and counseling of the individual and their family.

Pathogenic variants in these genes account for an estimated 70% of individuals with ALPS.

Gene Attribution to ALPS
CASP8 rare
CTLA4 rare
FAS ~70%
FASLG <1%
ITK rare
MAGT1 rare
PIK3CD rare
PRKCD rare
STAT3 rare

The following genes confer an increased risk of ALPS

  • in an autosomal dominant inheritance pattern – CASP10, CTLA4, FAS, FASLG, and PIK3CD
  • in an autosomal recessive inheritance pattern – CASP8, FADD, FASLG, PRKCD, and ITK
  • in an increased risk of ALPS in an X-linked pattern – MAGT1

ALPS is a rare primary immunodeficiency and the prevalence as this disorder is likely underdiagnosed.

This panel may be considered for individuals whose personal and/or family history is suggestive of a hereditary predisposition to ALPS, including any of the following:

  • chronic lymphadenopathy
  • elevated CD3+, TCRαβ+, CD4-, CD8-, DNT cells
  • defective lymphocyte apoptosis
  • a family history of ALPS

If the patient has undergone a bone marrow transplant prior to genetic testing or currently has a hematological malignancy with actively circulating tumor cells, testing a sample type not derived from blood (such as skin biopsy) is warranted. While we do not accept this sample type directly, we can accept gDNA derived from skin or muscle, but deletion/duplication analysis is not guaranteed for gDNA samples because the success rate varies based on sample quality. Please see our Sample Requirements for more details.

For proposed recommendations to genetic counseling, testing, and clinical management, please refer to

  1. Rao, VK. Approaches to Managing Autoimmune Cytopenias in Novel Immunological Disorders with Genetic Underpinnings Like Autoimmune Lymphoproliferative Syndrome. Front Pediatr. 2015; 3:65. PMID: 26258116
  2. Shah, S, et al. Autoimmune lymphoproliferative syndrome: an update and review of the literature. Curr Allergy Asthma Rep. 2014; 14(9):462. PMID: 25086580
  3. Chun, HJ, et al. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature. 2002; 419(6905):395-9. PMID: 12353035
  4. Niemela, J, et al. Caspase-8 Deficiency Presenting as Late-Onset Multi-Organ Lymphocytic Infiltration with Granulomas in two Adult Siblings. J. Clin. Immunol. 2015; 35(4):348-55. PMID: 25814141
  5. Kuehn, HS, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014; 345(6204):1623-7. PMID: 25213377
  6. Schubert, D, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat. Med. 2014; 20(12):1410-6. PMID: 25329329
  7. Price, S, et al. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood. 2014; 123(13):1989-99. PMID: 24398331
  8. Oliveira, JB, et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood. 2010; 116(14):e35-40. PMID: 20538792
  9. Teachey, DT, et al. Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS). Br. J. Haematol. 2010; 148(2):205-16. PMID: 19930184
  10. van, der, Burg, M, et al. Autoimmune lymphoproliferative syndrome (ALPS) in a child from consanguineous parents: a dominant or recessive disease?. Pediatr. Res. 2000; 47(3):336-43. PMID: 10709732
  11. Rieux-Laucat, F, et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science. 1995; 268(5215):1347-9. PMID: 7539157
  12. Wu, J, et al. Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. J. Clin. Invest. 1996; 98(5):1107-13. PMID: 8787672
  13. Bi, LL, et al. Dominant inhibition of Fas ligand-mediated apoptosis due to a heterozygous mutation associated with autoimmune lymphoproliferative syndrome (ALPS) Type Ib. BMC Med. Genet. 2007; 8:41. PMID: 17605793
  14. Linka, RM, et al. Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases. Leukemia. 2012; 26(5):963-71. PMID: 22289921
  15. Stepensky, P, et al. IL-2-inducible T-cell kinase deficiency: clinical presentation and therapeutic approach. Haematologica. 2011; 96(3):472-6. PMID: 21109689
  16. Belot, A, et al. Protein kinase cδ deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation. Arthritis Rheum. 2013; 65(8):2161-71. PMID: 23666743
  17. Oliveira, JB. The expanding spectrum of the autoimmune lymphoproliferative syndromes. Curr. Opin. Pediatr. 2013; 25(6):722-9. PMID: 24240292
  18. Nabhani, S, et al. STAT3 gain-of-function mutations associated with autoimmune lymphoproliferative syndrome like disease deregulate lymphocyte apoptosis and can be targeted by BH3 mimetic compounds. Clin. Immunol. 2017; 181:32-42. PMID: 28579554
  19. Milner, JD, et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood. 2015; 125(4):591-9. PMID: 25359994

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
CASP10 NM_032977.3
CASP8 NM_001228.4
CTLA4 NM_005214.4
FADD NM_003824.3
FAS NM_000043.5
FASLG NM_000639.2
ITK NM_005546.3
MAGT1 NM_032121.5
PIK3CD NM_005026.3
PRKCD NM_006254.3
STAT3 NM_139276.2

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

References

  1. Belot, A, et al. Protein kinase cδ deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation. Arthritis Rheum. 2013; 65(8):2161-71. PMID: 23666743
  2. Bi, LL, et al. Dominant inhibition of Fas ligand-mediated apoptosis due to a heterozygous mutation associated with autoimmune lymphoproliferative syndrome (ALPS) Type Ib. BMC Med. Genet. 2007; 8:41. PMID: 17605793
  3. Chun, HJ, et al. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature. 2002; 419(6905):395-9. PMID: 12353035
  4. Kuehn, HS, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014; 345(6204):1623-7. PMID: 25213377
  5. Linka, RM, et al. Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases. Leukemia. 2012; 26(5):963-71. PMID: 22289921
  6. Milner, JD, et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood. 2015; 125(4):591-9. PMID: 25359994
  7. Nabhani, S, et al. STAT3 gain-of-function mutations associated with autoimmune lymphoproliferative syndrome like disease deregulate lymphocyte apoptosis and can be targeted by BH3 mimetic compounds. Clin. Immunol. 2017; 181:32-42. PMID: 28579554
  8. Niemela, J, et al. Caspase-8 Deficiency Presenting as Late-Onset Multi-Organ Lymphocytic Infiltration with Granulomas in two Adult Siblings. J. Clin. Immunol. 2015; 35(4):348-55. PMID: 25814141
  9. Oliveira, JB, et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood. 2010; 116(14):e35-40. PMID: 20538792
  10. Oliveira, JB. The expanding spectrum of the autoimmune lymphoproliferative syndromes. Curr. Opin. Pediatr. 2013; 25(6):722-9. PMID: 24240292
  11. Price, S, et al. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood. 2014; 123(13):1989-99. PMID: 24398331
  12. Rao, VK. Approaches to Managing Autoimmune Cytopenias in Novel Immunological Disorders with Genetic Underpinnings Like Autoimmune Lymphoproliferative Syndrome. Front Pediatr. 2015; 3:65. PMID: 26258116
  13. Rieux-Laucat, F, et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science. 1995; 268(5215):1347-9. PMID: 7539157
  14. Schubert, D, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat. Med. 2014; 20(12):1410-6. PMID: 25329329
  15. Shah, S, et al. Autoimmune lymphoproliferative syndrome: an update and review of the literature. Curr Allergy Asthma Rep. 2014; 14(9):462. PMID: 25086580
  16. Stepensky, P, et al. IL-2-inducible T-cell kinase deficiency: clinical presentation and therapeutic approach. Haematologica. 2011; 96(3):472-6. PMID: 21109689
  17. Teachey, DT, et al. Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS). Br. J. Haematol. 2010; 148(2):205-16. PMID: 19930184
  18. Wu, J, et al. Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. J. Clin. Invest. 1996; 98(5):1107-13. PMID: 8787672
  19. van, der, Burg, M, et al. Autoimmune lymphoproliferative syndrome (ALPS) in a child from consanguineous parents: a dominant or recessive disease?. Pediatr. Res. 2000; 47(3):336-43. PMID: 10709732

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