Invitae Autoinflammatory Syndromes Panel

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  • Test code: 08120
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Test description

The Invitae Autoinflammatory Syndromes Panel analyzes 26 genes that are associated with bouts of systemic and localized inflammation, with or without periodic fevers, that lack an infectious cause. This test is useful for the diagnosis of patients who, based on clinical symptoms or abnormal laboratory findings, are suspected of having an autoinflammatory syndrome. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions.

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Primary panel (26 genes)

ADA2 ADAM17 CARD14 COPA ELANE IL10 IL10RA IL10RB IL1RN IL36RN LPIN2 MEFV MVK NFAT5 NLRC4 NLRP12 NLRP3 NOD2 PLCG2 PSMB8 PSTPIP1 RBCK1 SH3BP2 SLC29A3 TNFRSF1A TRNT1

Gene Disorder
ADA2 Polyarteritis nodosa and Sneddon syndrome
ADAM17 Inflammatory skin and bowel disease (ISBD)
CARD14 Pytiriasis rubra pilaris, psoriasis
COPA Autoimmune interstitial lung, joint, and kidney disease
ELANE Cyclic neutropenia
IL10 IL-10 deficiency
IL10RA IL-10Rα deficiency
IL10RB IL-10Rβ deficiency
IL1RN Interleukin 1 receptor antagonist deficiency
IL36RN Psoriasis
LPIN2 Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)
MEFV Familial Mediterranean fever
MVK* Mevalonate kinase deficiency, which includes: hyper IgD syndrome; mevalonic aciduria
NFAT5 NFAT5 haploinsufficiency
NLRC4 Familial cold autoinflammatory syndrome
NLRP12 Familial cold autoinflammatory syndrome
NLRP3 Cryopyrin-associated periodic fever syndrome (CAPS), which includes: Muckle-Wells syndrome; familial cold autoinflammatory syndrome 1; neonatal onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic cutaneous and articular syndrome (CINCA)
NOD2 Blau syndrome
PLCG2 Familial cold autoinflammatory syndrome
PSMB8 Autoinflammation, lipodystrophy, and dermatosis syndrome (ALDD)
PSTPIP1 Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome
RBCK1** RBCK1-deficiency associated with autoinflammatory syndrome and immunodeficiency
SH3BP2 Cherubism
SLC29A3 Hystiocytosis-lymphadenopathy
TNFRSF1A TNF receptor-associated periodic syndrome (TRAPS)
TRNT1 Sideroblastic anemia with B-cell deficiency

*This gene is also associated with autosomal dominant porokeratosis, which does not cause periodic fever syndrome.
**This gene is mainly associated with polyglucosan body myopathy that presents with autoinflammatory syndrome and immunodeficiency in some cases

Autoinflammatory syndromes are a group of inherited disorders that cause bouts of autoinflammatory symptoms, with and without periodic fevers, without an infectious cause. There is considerable overlap across clinical manifestations and even individuals with the same genetic defect present with variable symptoms. Common inflammatory signs are skin rash, joint pain, and swelling, although localized inflammation can occur at other sites (depending on the underlying genetic cause), such as in the bowel, pericardium or heart muscle, meninges, or mucous membranes. Kidney failure, hearing loss, vision problems, and joint contractures are some of the long-term complications that may occur as a result of progressive kidney damage caused by some periodic fever syndromes. Familial Mediterranean fever is the most common of the periodic fever syndromes; patients with this condition typically have recurrent abdominal pain. Inflammatory bowel disease is characterized by chronic inflammation of the intestinal tract. While Crohn’s disease may involve any part of the gastrointestinal tract, it is most frequent in the terminal ileum and colon, however ulcerative colitis is limited to rectal and colonic mucosal layers. The length and frequency of attacks varies between the different underlying genetic conditions and even between patients with the same genetic condition. Most patients have their first attack in childhood, but symptom onset can range from childhood to adulthood. Early diagnosis and treatment is critical for reducing the morbidity and mortality associated with these disorders. Different syndromes may have differences in treatment regimens, and newer, disorder-specific therapies are in clinical trials. This highlights the importance of an accurate molecular diagnosis, necessary to understand the long-term complications and to tailor appropriate treatments.

The clinical sensitivity for this test is unknown. Monogenic autoinflammatory syndromes are clinically and genetically heterogeneous, and the percentage of patients with a monogenic autoinflammatory syndrome and a pathogenic variant(s) in one of the genes offered in this panel has not been determined.

Periodic fever syndromes are inherited in either an autosomal recessive or autosomal dominant manner, depending on the underlying gene condition:

Gene Disorder Inheritance
ADA2 Polyarteritis nodosa and Sneddon syndrome autosomal recessive
ADAM17 Inflammatory skin and bowel disease (ISBD) autosomal recessive
CARD14 Pytiriasis rubra pilaris, psoriasis autosomal dominant
COPA Autoimmune interstitial lung, joint, and kidney disease autosomal dominant
ELANE Neutropenia with recurrent fever and skin, oropharyngeal, and cervical lymph node inflammation autosomal dominant
IL10 Inflammatory bowel disease (IBD) autosomal recessive
IL10RA Inflammatory bowel disease (IBD) autosomal recessive
IL10RB Inflammatory bowel disease (IBD) autosomal recessive
IL1RN Interleukin 1 receptor antagonist deficiency autosomal recessive
IL36RN Psoriasis autosomal recessive
LPIN2 Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome) autosomal recessive
MEFV Familial Mediterranean fever autosomal recessive and rarely autosomal dominant
MVK* Mevalonate kinase deficiency, which includes: hyper IgD syndrome; mevalonic aciduria autosomal recessive
NLRC4 Familial cold autoinflammatory syndrome autosomal dominant
NLRP12 Familial cold autoinflammatory syndrome autosomal dominant
NLRP3 Cryopyrin-associated periodic fever syndrome (CAPS), which includes: Muckle-Wells syndrome; familial cold autoinflammatory syndrome 1; neonatal onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic cutaneous and articular syndrome (CINCA) autosomal dominant
NOD2 Blau syndrome autosomal dominant
PLCG2 Familial cold autoinflammatory syndrome autosomal dominant
PSMB8 Autoinflammation, lipodystrophy, and dermatosis syndrome (ALDD) autosomal recessive
PSTPIP1 Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome autosomal dominant
RBCK1** RBCK1-deficiency associated with autoinflammatory syndrome and immunodeficiency autosomal recessive
SH3BP2 Cherubism autosomal dominant
SLC29A3 Hystiocytosis-lymphadenopathy autosomal recessive
TNFRSF1A TNF receptor-associated periodic syndrome (TRAPS) autosomal dominant
TNFRSF11A Autoinflammatory disease autosomal dominant
TRNT1 Sideroblastic anemia with B-cell deficiency autosomal recessive

*This gene is also associated with autosomal dominant porokeratosis, which does not cause periodic fever syndrome.
**This gene is mainly associated with polyglucosan body myopathy that presents with autoinflammatory syndrome and immunodeficiency in some cases

The prevalence of autoinflammatory syndromes is dependent on the underlying condition. Formal prevalence estimates have not been determined for many of the monogenic autoinflammatory syndromes due to their rare nature; however, the prevalence of familial Mediterranean fever, the most common of the periodic fever syndromes, is known to vary greatly based on ethnicity. Reports have suggested a prevalence from 1 in 40,000 in the U.S. to 1 in 250 in other populations (PMID: 16979528).

  1. Caso, F, et al. Monogenic autoinflammatory syndromes: state of the art on genetic, clinical, and therapeutic issues. Int J Rheumatol. 2013; 2013:513782. PMID: 24282415
  2. D'Arcangelo, G, Aloi, M. Inflammatory Bowel Disease-Unclassified in Children: Diagnosis and Pharmacological Management. Paediatr Drugs. 2017; 19(2):113-120. PMID: 28150131
  3. Demirkaya, E, et al. Performance of Different Diagnostic Criteria for Familial Mediterranean Fever in Children with Periodic Fevers: Results from a Multicenter International Registry. J. Rheumatol. 2015. PMID: 26568587
  4. El-Shanti, H, Ferguson, P. Majeed Syndrome. 2008 Sep 23. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301735
  5. Federici, S, et al. Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers. Ann. Rheum. Dis. 2015; 74(5):799-805. PMID: 25637003
  6. Fujikura, K. Global epidemiology of Familial Mediterranean fever mutations using population exome sequences. Mol Genet Genomic Med. 2015; 3(4):272-82. PMID: 26247045
  7. Giat, E, Lidar, M. Cryopyrin-associated periodic syndrome. Isr. Med. Assoc. J. 2014; 16(10):659-61. PMID: 25438464
  8. Griffith, LM, et al. Improving cellular therapy for primary immune deficiency diseases: recognition, diagnosis, and management. J. Allergy Clin. Immunol. 2009; 124(6):1152-60.e12. PMID: 20004776
  9. Gülhan, B, et al. Diagnostic dilemma in autoinflammatory disease in two patients: does the name matter?. Turk. J. Pediatr. 2013; 55(3):315-8. PMID: 24217079
  10. Hofer, M, et al. A child with a systemic febrile illness - differential diagnosis and management. Best Pract Res Clin Rheumatol. 2006; 20(4):627-40. PMID: 16979528
  11. Jackson, BD, et al. Clinicians' adherence to international guidelines in the clinical care of adults with inflammatory bowel disease. Scand. J. Gastroenterol. 2017; 52(5):536-542. PMID: 28128675
  12. Larsen, L, et al. The Danish National Registry for Biological Therapy in Inflammatory Bowel Disease. Clin Epidemiol. 2016; 8:607-612. PMID: 27822107
  13. Livneh, A, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997; 40(10):1879-85. PMID: 9336425
  14. Pathak, S, et al. Autoinflammatory diseases: update on classification diagnosis and management. J. Clin. Pathol. 2017; 70(1):1-8. PMID: 27646526
  15. Shohat, M, Halpern, GJ. Familial Mediterranean Fever. 2000 Aug 08. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301405
  16. Ter, Haar, N, et al. Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review. Ann. Rheum. Dis. 2013; 72(5):678-85. PMID: 22753383
  17. Yalçinkaya, F, et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford). 2009; 48(4):395-8. PMID: 19193696
  18. ter, Haar, NM, et al. Recommendations for the management of autoinflammatory diseases. Ann. Rheum. Dis. 2015; 74(9):1636-44. PMID: 26109736

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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ADA2 NM_001282225.1
ADAM17 NM_003183.5
CARD14 NM_024110.4
COPA NM_004371.3
ELANE NM_001972.2
IL10 NM_000572.2
IL10RA NM_001558.3
IL10RB NM_000628.4
IL1RN NM_173841.2
IL36RN NM_012275.2
LPIN2 NM_014646.2
MEFV NM_000243.2
MVK NM_000431.3
NFAT5 NM_138714.3
NLRC4 NM_021209.4
NLRP12 NM_144687.3
NLRP3 NM_004895.4
NOD2 NM_022162.2
PLCG2 NM_002661.4
PSMB8 NM_148919.3
PSTPIP1 NM_003978.3
RBCK1 NM_031229.3
SH3BP2 NM_003023.4
SLC29A3 NM_018344.5
TNFRSF1A NM_001065.3
TRNT1 NM_182916.2