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.
CASP8 CTLA4 FAS FASLG ITK MAGT1 PIK3CD PRKCD STAT3
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.
CASP8 CTLA4 FAS FASLG ITK MAGT1 PIK3CD PRKCD STAT3
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
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
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:
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
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 |