This test is currently unavailable. No alternative test is available via Mayo Clinic Laboratories. For additional details, see test update here. Contact Laboratory Resource Coordinators with questions.
Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of autoinflammatory syndromes and related disorders
Establishing a diagnosis of autoinflammatory disease, and in some cases guiding management and allowing for surveillance of disease features
Identification of pathogenic variants within genes known to be associated with autoinflammatory disorders allowing for predictive testing of at-risk family members
This test uses next-generation sequencing to test for variants in the CARD14, IL10RA, IL10RB, IL1RN, IL36RN, ISG15, LPIN2, MEFV, MVK, NLRP12, NLRP3 (CIAS1), NOD2 (CARD15), PLCG2, PSMB8, PSTPIP1 (CD2BP1), RBCK1 (HOIL1), SH3BP2, and TNFRSF1A genes.
Identification of a pathogenic variant may assist with prognosis, clinical management, familial screening, and genetic counseling.
This test includes next-generation sequencing and supplemental Sanger sequencing to evaluate for the genes listed on the panel.
| Test Id | Reporting Name | Available Separately | Always Performed |
|---|---|---|---|
| CULFB | Fibroblast Culture for Genetic Test | Yes | No |
For skin biopsy or cultured fibroblast specimens, fibroblast culture testing will be performed at an additional charge. If viable cells are not obtained, the client will be notified.
Custom Sequence Capture and Targeted Next-Generation Sequencing followed by Polymerase Chain Reaction (PCR) and Supplemental Sanger Sequencing
Autoinflammation
Autoinflammatory bone disease
Blau syndrome
CARD14
Chronic atypical neutrophilic dermatitis with lipodystrophy (CANDLE)
Chronic infantile neurological cutaneous and articular syndrome (CINCA)
Deficiency of interleukin 1 receptor antagonist (DIRA)
Deficiency of interleukin 36 receptor antagonist (DITRA)
Familial cold autoinflammatory syndrome (FCAS1/FCAS2)
Familial Mediterranean fever (FMF)
Hyperimmunoglobulinemia D syndrome (HIDS)
IL10RA
IL10RB
IL1RN
IL36RN
Inflammatory bowel disease
ISG15
Japanese autoinflammatory syndrome with lipodystrophy (JASL)
JMP (joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy)
LPIN2
MEFV
Majeed syndrome
Mevalonic aciduria
Muckle-Wells syndrome
MVK
Neonatal onset multisystem inflammatory disease (NOMID)
NLRP12
NLRP3 (CIAS1)
NOD2 (CARD15)
Pediatric granulomatous arthritis
PLCG2
PLC-gamma2 associated antibody deficiency and immune dysregulation (PLAID)
Proteasome-associated autoinflammatory syndrome (PRASS)
PSMB8
PSTPIP1 (CD2BP1)
Psoriasis 2
Pustular psoriasis
Pyogenic sterile arthritis pyoderma gangrenosum acne (PAPA)
RBCK1 (HOIL1)
SH3BP2
TNFRSF1A
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)
Very early onset inflammatory bowel disease (VEOIBD)
Primary Immunodeficiency
Pityriasis rubra pilaris
For skin biopsy or cultured fibroblast specimens, fibroblast culture testing will be performed at an additional charge. If viable cells are not obtained, the client will be notified.
Varies
Targeted testing for familial variants (also called site-specific or known mutations testing) is available for the genes on this panel.
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.
Patient Preparation: A previous bone marrow transplant from an allogenic donor 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 whole blood 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,
PerkinElmer 226 (formerly Ahlstrom 226) filter paper, or blood spot collection card
Specimen Volume: 2 to 5 Blood spots
Collection Instructions:
1. An alternative blood collection option for a patient 1 year of age or older is a fingerstick. See How to Collect Dried Blood Spot Samples via fingerstick.
2. Let blood dry on the filter paper at ambient temperature in a horizontal position for a minimum of 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
Additional Information:
1. Due to lower concentration of DNA yielded from blood spots, it is possible that additional specimen may be required to complete testing.
2. For collection instructions, see Blood Spot Collection Instructions.
3. For collection instructions in Spanish, see Blood Spot Collection Card-Spanish Instructions (T777).
4. For collection instructions in Chinese, see Blood Spot Collection Card-Chinese Instructions (T800).
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 CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 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 CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 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
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.
Whole blood: 1 mL
| Specimen Type | Temperature | Time | Special Container |
|---|---|---|---|
| Varies | Varies | ||
Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of autoinflammatory syndromes and related disorders
Establishing a diagnosis of autoinflammatory disease, and in some cases guiding management and allowing for surveillance of disease features
Identification of pathogenic variants within genes known to be associated with autoinflammatory disorders allowing for predictive testing of at-risk family members
This test uses next-generation sequencing to test for variants in the CARD14, IL10RA, IL10RB, IL1RN, IL36RN, ISG15, LPIN2, MEFV, MVK, NLRP12, NLRP3 (CIAS1), NOD2 (CARD15), PLCG2, PSMB8, PSTPIP1 (CD2BP1), RBCK1 (HOIL1), SH3BP2, and TNFRSF1A genes.
Identification of a pathogenic variant may assist with prognosis, clinical management, familial screening, and genetic counseling.
For skin biopsy or cultured fibroblast specimens, fibroblast culture testing will be performed at an additional charge. If viable cells are not obtained, the client will be notified.
Autoinflammatory disorders include several monogenic defects associated with abnormal activation of the innate immune system leading to clinically evident inflammation and high levels of acute-phase reactants. These disorders typically present in childhood, often manifesting with unexplained fevers. While these features can mimic infections or hematological neoplasias, the inflammatory lesions are non-neoplastic and sterile. While periodic fever adenitis pharyngitis aphthous ulcer syndrome (aphthous stomatitis, pharyngitis, and adenitis), systemic juvenile idiopathic arthritis (sJIA), adult-onset Still disease, and Behcet disease overlap phenotypically with autoinflammatory conditions, a genetic cause of these disorders has not been identified and, therefore, they are not included on this panel. Several of the autoinflammatory conditions represented on this panel are responsive to interleukin-1 (IL-1) blocking therapies; therefore, determining the underlying genetic cause may help guide treatment decisions.
Monogenic autoinflammatory conditions include the periodic fever syndromes (ie, familial Mediterranean fever, cryopyrinopathy-associated periodic syndrome, Muckle-Wells syndrome, familial cold autoinflammatory syndrome, neonatal onset multisystem inflammatory disease or chronic infantile neurologic cutaneous and articular syndrome, tumor necrosis factor [TNF] receptor-associated periodic syndrome, hyper IgD syndrome/Mevalonate kinase deficiency), diseases with pyogenic lesions (ie, deficiency of Il-1 receptor antagonist [DIRA]; pyogenic arthritis, pyoderma gangrenosum and acne [PAPA]; Majeed syndrome), diseases with granulomatous lesions (ie, Blau syndrome), diseases with psoriasis (ie, deficiency of interleukin 36-receptor antagonist [DITRA]); diseases with panniculitis-induced lipodystrophy (JMP syndrome, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome [CANDLE], Nakajo-Nishimura syndrome [NNS], proteasome-associated autoinflammatory syndromes [PRAAS]). DITRA and CARD14-mediated psoriasis (CAMPS) both present with pustular skin lesions and early-onset inflammatory bowel disease . See the table for a summary of genes included in this panel, associated diseases, and the mode of inheritance.
NOD2-associated autoinflammatory disease (NAID), also known as Yao syndrome, is a newly described clinical entity characterized by recurrent fever, dermatitis, and inflammatory arthritis along with GI symptoms in a majority of the patients. Variants in NOD2 have been associated with NAID; however, the variants that have been implicated to date are common variants that confer risk for development of the disorder and are not diagnostic. These common variants are not included in the report for this panel; however, a list of all common variants identified is available by request.
While several of the autoinflammatory conditions, including those without a known genetic basis, are responsive to IL-1 blocking therapies, PRAAS, CANDLE, DITRA, and CAMPS are not responsive to IL-1 blockade. Anakinra, rilonacept, and canakinumab are several examples of medications that target IL-1.
The NOD-like receptors (NLR), which include 23 family members in humans, are an integral part of the innate immune system. NLR are involved in the formation of the inflammasome, of which the NLRP3 (NALP3) inflammasome is most relevant to human disease and is responsible for activation of the proinflammatory cytokine IL-1 beta.
Table. Genes included in this panel
| Gene symbol (alias) | Protein | OMIM | Incidence | Inheritance | Phenotype disorder |
| CARD14 | Caspase recruitment domain-containing protein 14 isoform 1 | 607211 | Rare | AD | Pityriasis rubra pilaris, psoriasis 2 (CAMPS) |
| IL10RA | Interleukin-10 receptor subunit alpha precursor | 146933 | Rare | AR | Very early onset inflammatory bowel disease 28 (VEOIBD) |
| IL10RB | Interleukin-10 receptor subunit beta precursor | 123889 | Rare | AR | Very early onset inflammatory bowel disease 25 (VEOIBD) |
| IL1RN | Interleukin-1 receptor antagonist protein isoform 2 | 147679 | Rare | AR | Deficiency of interleukin 1 receptor antagonist (DIRA) |
| IL36RN | Interleukin-36 receptor antagonist protein | 605507 | Rare | AR | Pustular psoriasis 14, deficiency of IL36 receptor antagonist (DITRA) |
| ISG15 | Ubiquitin-like protein ISG15 precursor | 147571 | Rare | AR | Immunodeficiency 38 |
| LPIN2 | Phosphatidate phosphatase LPIN2 | 605519 | Primarily identified in Arab ethnicities | AR | Majeed syndrome |
| MEFV | Pyrin isoform 1 | 608107 | Primarily identified in Armenian, Arab, Turkish, Italian, and Jewish ethnicities | AR (most), AD (rarely) | Familial Mediterranean fever (FMF) |
| MVK | Mevalonate kinase isoform a | 251170 | Primarily identified in Caucasians of western European ancestry | AR/AD | Hyperimmunoglobulinemia D syndrome (HIDS), Mevalonate kinase-associated periodic fever syndrome, Mevalonic aciduria, Porokeratosis 3, multiple types (AD) |
| NLRP12 (NALP12) | NACHT, leucine rich repeat (LRR) and PYD domains-containing protein 12 isoform 2 | 609648 | Rare | AD | Familial cold autoinflammatory syndrome 2 (FCAS2) |
| NLRP3 (NALP3) (CIAS1) | NACHT, LRR, and PYD domains-containing protein 3 isoform a | 606416 | Primarily identified in Caucasians of western European ancestry | AD | Familial cold autoinflammatory syndrome 1 (FCAS1), Muckle-Wells syndrome; Neonatal onset multisystem inflammatory disease (NOMID)/chronic infantile neurological cutaneous and articular syndrome (CINCA) |
| NOD2 (CARD15) | Nucleotide-binding oligomerization domain-containing protein 2 isoform 1 | 605956 | Rare | AD | Blau syndrome, Early-onset Sarcoidosis, Inflammatory bowel disease 1 Pediatric granulomatous arthritis (PGA) |
| PLCG2 | 1-Phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 | 600220 | Rare | AD | PLC gamma 2-associated antibody deficiency and immune dysregulation (PLAID), autoinflammation and PLC gamma 2-associated antibody deficiency and immune dysregulation (APLAID) |
| PSMB8 | Proteasome subunit beta type-8 isoform E2 precursor | 177046 | Rare | AR | CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy); JMP (joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy); PRASS (proteasome-associated auto-inflammatory syndrome); JASL (Japanese autoinflammatory syndrome with lipodystrophy) |
| PSTPIP1 (CD2BP1) | Proline-serine-threonine phosphatase-interacting protein 1 | 606347 | Rare | AD | Pyogenic sterile arthritis |
| RBCK1 (HOIL1) | RanBP-type and C3HC4-type zinc finger-containing protein 1 isoform 2 | 610924 | Rare | AR | Polyglucosan body myopathy 1 with or without immunodeficiency; chronic autoinflammation, invasive bacterial infections, muscle amylopectinosis |
| SH3BP2 | SH3 domain-binding protein 2 isoform a | 602104 | Rare | AD | Cherubism, autoinflammatory bone disease |
| TNFRSF1A | Tumor necrosis factor receptor superfamily member 1A precursor | 191190 | Primarily identified in Caucasians of western European ancestry | AD | Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) |
An interpretive report will be provided.
Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics (ACMG) recommendations as a guideline.(1) 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.
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.
If testing was performed because of a family history of autoinflammatory disease, it is important 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 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 pathogenic variants 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 including benign, likely benign, and high minor allele frequency (>1%) risk-associated variants detected is available from the lab upon request after results are received.
Contact the laboratory if additional information is required regarding the transcript or human genome assembly used for the analysis of this patient's results.
1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-424
2. Ozen S, Bilginer T: A clinical guide to autoinflammatory diseases: FMF and next of kin. Nature Rev. Rheumatol. 2014;10:135-147
3. Canna SW, Goldbach-Mansky R: New monogenic autoinflammatory diseases-a clinical overview. Semin Immunopathol. 2015;37:387-394
4. Henderson C, Goldbach-Mansky R: Monogenic IL-1-mediated autoinflammatory and immunodeficiency syndromes: finding the right balance in response to danger signals. Clin Immunol. 2010;135:210-222
5. Caso F, Galozzi P, Costa L, et al: Autoinflammatory granulomatous diseases: from Blau syndrome and early-onset sarcoidosis to NOD2-mediated disease and Crohn's disease. RMD Open. 2015;1:e000097
6. Stern SM, Ferguson PJ: Autoinflammatory bone diseases. Rheum Dis Clin North Am. 2013;39:735-749
7. Martinon F, Aksentijevich I: New Players driving inflammation in monogenic autoinflammatory diseases. Nat Rev Rheumatol. 2015;11:11-20
8. Jesus AA, Goldbach-Mansky R: IL-1 blockade in autoinflammatory syndromes. Annu Rev Med. 2014;65:223-244
9. 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
Genes analyzed: CARD14, IL10RA, IL10RB, IL1RN, IL36RN, ISG15, LPIN2, MEFV, MVK, NLRP12, NLRP3 (CIAS1), NOD2 (CARD15), PLCG2, PSMB8, PSTPIP1 (CD2BP1), RBCK1 (HOIL1), SH3BP2, TNFRSF1A
Monday
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.
81443
| Test Id | Test Order Name | Order LOINC Value |
|---|---|---|
| AUTOP | Autoinflammatory PID Gene Panel | In Process |
| Result Id | Test Result Name |
Result LOINC Value
Applies only to results expressed in units of measure originally reported by the performing laboratory. These values do not apply to results that are converted to other units of measure.
|
|---|---|---|
| BA3878 | Gene(s) Evaluated | 48018-6 |
| BA3879 | Result Summary | 50397-9 |
| BA3880 | Result Details | 82939-0 |
| BA3881 | Interpretation | 69047-9 |
| BA3882 | Additional Information | 48767-8 |
| BA3883 | Method | 85069-3 |
| BA3884 | Disclaimer | 62364-5 |
| BA3885 | Reviewed by | 18771-6 |