Test ID: AUTOP    
Autoinflammatory Primary Immunodeficiency (PID) Gene Panel, 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 and cryopreservation 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

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

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