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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
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Invitae Autoinflammatory Syndromes Panel

Test description

The Invitae Autoinflammatory Syndromes Panel analyzes 109 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 (72 genes)

ACP5 ADA ADA2 ADAM17 ADAR AICDA BTK CARD14 CD3G CD40LG COPA CTLA4 CYBA CYBB DCLRE1C DKC1 DOCK8 ELANE FOXP3 G6PC3 ICOS IFIH1 IL10 IL10RA IL10RB IL1RN IL21 IL2RA IL2RG IL36RN ITGB2 LIG4 LPIN2 LRBA MEFV MVK NCF2 NCF4 NFAT5 NLRC4 NLRP12 NLRP3 NOD2 PIK3CD PIK3R1 PLCG2 PSMB8 PSTPIP1 RAG1 RAG2 RBCK1 RNASEH2A RNASEH2B RNASEH2C RTEL1 SAMHD1 SH2D1A SH3BP2 SLC29A3 SLC37A4 STAT1 STAT3 STIM1 STXBP2 TMEM173 TNFRSF1A TREX1 TRNT1 TTC7A WAS XIAP ZAP70

Add-on Autoimmunity Genes (37 genes)

Generally, autoinflammatory disorders are characterized by episodic inflammation due to inappropriate activation of the innate immune response whereas autoimmune disorders are caused by defects in adaptive immunity leading to loss of self-tolerance. Autoimmune and autoinflammatory diseases share clinical manifestations and cross-over between these disease groups has been recognized (PMID: 24164192). Both types of conditions result in self-directed inflammation in the absence of a known trigger, and recent studies suggest considerable overlap in molecular pathways involved in both groups of conditions (PMID: 29099860). Genes associated with autoimmune disorders can be added to this panel at no additional charge.

AIRE AP3B1 BLOC1S6 CASP10 CASP8 CD27 CR2 FADD FAS FASLG IL21R ITCH ITK LYST MAGT1 NFKB2 NFKBIA ORAI1 PNP PRF1 PRKCD RAB27A RAC2 RFX5 RFXANK RFXAP RMRP SLC7A7 STAT5B STX11 TBX1 TNFRSF13B TNFRSF13C TNFSF12 TPP2 UNC13D UNG




Gene Disorder Protein name Protein symbol
ACP5 Spondyloenchondro-dysplasia with immune dysregulation tartrate-resistant acid phosphatase TRAP
ADA Adenosine deaminase (ADA) deficiency adenosine deaminase ADA
ADA2 ADA2 deficiency cat eye syndrome chromosome region, candidate 1 CECR1
ADAM17 ADAM17 deletion tumor necrosis factor-alpha converting enzyme TACE
ADAR ADAR1 deficiency, Aicardi-Goutieres syndrome 6 RNA-specific adenosine deaminase ADAR
AICDA AID deficiency activation-induced cytidine deaminase AID
BTK BTK deficiency Bruton agammaglobulinemia tyrosine kinase BTK
CARD14 CAMPS (CARD14 mediated psoriasis) caspase recruitment domain-containing protein 14 CARD14
CD3G CD3γ deficiency CD3-gamma CD3-gamma
CD40LG CD40 ligand deficiency CD40 ligand CD40LG
COPA COPA defect, autoimmune interstitial lung, joint, and kidney disease (AILJK) Coatamer protein complex, subunit alpha COPA
CTLA4 CTLA4 deficiency (ALPSV) Cytotoxic T Lymphocyte antigen 4 CTLA4
CYBA Autosomal recessive CGD 22kD-phagocyte oxidase p22-phox
CYBB X-linked chronic granulomatous disease (CGD) 91kD-phagocyte oxidase p91-phox
DCLRE1C DCLRE1C (Artemis) deficiency Artemis Artemis
DKC1 XL-DKC due to Dyskerin deficiency dyskerin DKC1
DOCK8 DOCK8 deficiency dedicator of cytokinesis 8 DOCK8
ELANE Elastase deficiency (SCN1), cyclic neutropenia elastase ELANE
FOXP3 IPEX, immune dysregulation, polyendocrinopathy, enteropathy X-linked forkhead box p3 FOXP3
G6PC3 G6PC3 deficiency (SCN4) glucose-6-phosphatase beta G6PC3
ICOS ICOS deficiency inducible T-cell costimulator ICOS
IFIH1 Aicardi-Goutieres syndrome 7 interferon-induced helicase domain-containing protein 1 IFIH1
IL10 IL-10 deficiency interleukin-10 IL-10
IL10RA IL-10Rα deficiency interleukin-10 receptor alpha IL-10R1
IL10RB IL-10Rβ deficiency interleukin-10 receptor beta IL-10R2
IL1RN DIRA -Deficiency of the Interleukin 1 Receptor Antagonist interleukin-1 receptor antagonist IL-1RN
IL21 IL-21 deficiency IL-21 deficiency IL-21
IL2RA CD25 deficiency CD25 CD25
IL2RG γc deficiency interleukin receptor common gamma chain gamma-c
IL36RN DITRA – Deficiency of IL-36 receptor antagonist interleukin-36 receptor antagonist IL-36RN
ITGB2 Leukocyte adhesion deficiency type 1 integrin beta 2 ITGB2
LIG4 DNA ligase IV deficiency DNA ligase IV LIG4
LPIN2 Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome) lipin 2 LIPIN2
LRBA LRBA deficiency lipopolysaccharide responsive beige-like anchor protein LRBA
MEFV Familial Mediterranean Fever pyrin PYRIN
MVK* Mevalonate kinase deficiency mevalonate kinase MVK
NCF2 Autosomal recessive CGD 67kD-phagocyte oxidase p67-phox
NCF4 Autosomal recessive CGD 40kD-phagocyte oxidase p40-phox
NFAT5 NFAT5 haploinsufficiency tonicity-responsive enhancer-binding protein TONEBP
NLRC4 NLRC4-MAS (macrophage activation syndrome), Familial cold autoinflammatory syndrome 4 NLR family, CARD containing 4 NLRC4
NLRP12 Familial cold autoinflammatory syndrome 2 NACHT domain-, leucine-rich repeat-, and PYD-containing protein 12 NALP12
NLRP3 Muckle-Wells syndrome, Familial cold autoinflammatory syndrome 1, Neonatal onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA) cryopyrin cryopyrin
NOD2 Blau syndrome caspase recruitment domain-containing protein 15 CARD15
PIK3CD Activated PI3K-δ p110-delta protein p110-delta
PIK3R1 PI3KR1 deficiency, PI3KR1 loss of function p85-alpha protein p85-alpha
PLCG2 PLAID (PLCγ2 associated antibody deficiency and immune dysregulation), Familial cold autoinflammatory syndrome phospholipase C gamma 2 PLCG2
PSMB8 CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy) proteasome subunit, beta-type 8 PSMB8
PSTPIP1 Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome CD2 antigen-binding protein 1 C2BP1
RAG1 RAG 1 deficiency recombinase activating gene 1 RAG1
RAG2 RAG 2 deficiency recombinase activating gene 2 RAG2
RBCK1** Polyglucosan body myopathy, early-onset, with or without immunodeficiency (PBMEI) heme-oxidized IRP2 ubiquitin ligase 1 HOIL1
RNASEH2A RNASEH2A deficiency, Aicardi-Goutieres syndrome 4 ribonuclease H2 subunit A RNASEH2A
RNASEH2B RNASEH2B deficiency, Aicardi-Goutieres syndrome 2 ribonuclease H2 subunit B RNASEH2B
RNASEH2C RNASEH2C deficiency, Aicardi-Goutieres syndrome 3 ribonuclease H2 subunit C RNASEH2C
RTEL1 AR-DKC due to regulator of telomere elongation (RTEL1) deficiency regulator of telomere elongation helicase 1 RTEL1
SAMHD1 SAMHD1 deficiency, Aicardi-Goutieres syndrome 5 SAM domain and HD domain containing protein 1 SAMHD1
SH2D1A SH2D1A deficiency (XLP1) SH2 domain protein 1A SH2D1A
SH3BP2 Cherubism SH3 domain binding protein 2 SH3BP2
SLC29A3 SLC29A3 mutation equilibrative nucleoside transporter 3 SLC29A3
SLC37A4 Glycogen storage disease type 1b glucose-6-phosphate transporter 1 G6PT1
STAT1 STAT1 deficiency signal transducer and activator of transcription 1 STAT1
STAT3 AD-HIES (Job or Buckley Syndrome), STAT3 GOF mutations signal transducer and activator of transcription 3 STAT3
STIM1 STIM1 deficiency stromal interaction molecule 1 STIM1
STXBP2 STXBP2 / Munc18-2 deficiency (FHL5) munc18-2 MUNC18-2
TMEM173 STING–associated vasculopathy, infantile onset stimulator of interferon genes STING
TNFRSF1A (TNF receptor-associated periodic syndrome (TRAPS) tumor necrosis factor receptor 1 TNFR1
TREX1 TREX1 deficiency, Aicardi-Goutieres syndrome   3-prime repair exonuclease 1 TREX1
TRNT1 TRNT1 deficiency tRNA nucleotidyltransferase, CCA-adding 1 TRNT1
TTC7A Immunodeficiency with multiple intestinal atresias tetratricopeptide repeat (TPR) domain containing protein 7A TTC7A
WAS Wiskott-Aldrich syndrome, X-linked neutropenia/ myelodysplasia WAS protein WASP
XIAP XIAP deficiency (XLP2) baculoviral IAP-repeat containing protein 4 BIRC4
ZAP70 ZAP-70 deficiency protein tyrosine kinase ZAP70 ZAP70

*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 or without periodic fevers, in the absence of an infectious trigger or injury. 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. This test includes genes for periodic fever syndromes such as Familial Cold Autoinflammatory syndrome and Familial Mediterranean fever, as well as genes associated with monogenic inflammatory bowel disease, which is characterized by chronic inflammation of the intestinal tract. Different autoinflammatory 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.

Four common variants in MEFV: c.442G>C (p.Glu148Gln), c.1105C>T (p.Pro369Ser), c.329T>C (p.Leu110Pro), and c.1223G>A (p.Arg408Gln), are not reported in our Primary report as they are classified as Likely Benign. If present, these variants would be listed in our Supplemental report, which is available upon request.

Two common variants in NOD2: c.2104C>T (p.Arg702Trp) and IVS8+158 (c.2798+158C>T) have been described in association with Yao syndrome (PMID: 26070941, 23102769). Please note that the c.2104C>T (p.Arg702Trp) variant is classified as an increased risk allele for Crohn’s disease at Invitae and the c.2798+158C>T deep intronic variant is outside of our reportable range and is not analyzed as part of this test.

The genes on this panel are inherited in multiple patterns, including autosomal dominant, autosomal recessive, and X-linked.

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. 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
  2. Giat, E, Lidar, M. Cryopyrin-associated periodic syndrome. Isr. Med. Assoc. J. 2014; 16(10):659-61. PMID: 25438464
  3. 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
  4. Fujikura, K. Global epidemiology of Familial Mediterranean fever mutations using population exome sequences. Mol Genet Genomic Med. 2015; 3(4):272-82. PMID: 26247045
  5. 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
  6. Livneh, A, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997; 40(10):1879-85. PMID: 9336425
  7. 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
  8. Federici, S, et al. Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers. Ann. Rheum. Dis. 2015; 74(5):799-805. PMID: 25637003
  9. 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
  10. Shohat, M, Halpern, GJ. Familial Mediterranean Fever. 2000 Aug 08. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301405
  11. El-Shanti, H, Ferguson, P. Majeed Syndrome. 2008 Sep 23. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301735
  12. 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
  13. Larsen, L, et al. The Danish National Registry for Biological Therapy in Inflammatory Bowel Disease. Clin Epidemiol. 2016; 8:607-612. PMID: 27822107
  14. Pathak, S, et al. Autoinflammatory diseases: update on classification diagnosis and management. J. Clin. Pathol. 2017; 70(1):1-8. PMID: 27646526
  15. 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
  16. 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
  17. ter, Haar, NM, et al. Recommendations for the management of autoinflammatory diseases. Ann. Rheum. Dis. 2015; 74(9):1636-44. PMID: 26109736
  18. D'Arcangelo, G, Aloi, M. Inflammatory Bowel Disease-Unclassified in Children: Diagnosis and Pharmacological Management. Paediatr Drugs. 2017; 19(2):113-120. PMID: 28150131
  19. Ciccarelli, F, et al. An update on autoinflammatory diseases. Curr. Med. Chem. 2014; 21(3):261-9. PMID: 24164192
  20. Arakelyan, A, et al. Autoimmunity and autoinflammation: A systems view on signaling pathway dysregulation profiles. PLoS ONE. 2017; 12(11):e0187572. PMID: 29099860

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
ACP5 NM_001111035.2
ADA NM_000022.2
ADA2 NM_001282225.1
ADAM17 NM_003183.5
ADAR NM_001111.4
AICDA NM_020661.2
AIRE NM_000383.3
AP3B1 NM_003664.4
BLOC1S6 NM_012388.3
BTK NM_000061.2
CARD14 NM_024110.4
CASP10 NM_032977.3
CASP8 NM_001228.4
CD27 NM_001242.4
CD3G NM_000073.2
CD40LG NM_000074.2
COPA NM_004371.3
CR2 NM_001006658.2
CTLA4 NM_005214.4
CYBA NM_000101.3
CYBB NM_000397.3
DCLRE1C NM_001033855.2
DKC1 NM_001363.4
DOCK8 NM_203447.3
ELANE NM_001972.2
FADD NM_003824.3
FAS NM_000043.5
FASLG NM_000639.2
FOXP3 NM_014009.3
G6PC3 NM_138387.3
ICOS NM_012092.3
IFIH1 NM_022168.3
IL10 NM_000572.2
IL10RA NM_001558.3
IL10RB NM_000628.4
IL1RN NM_173841.2
IL21 NM_021803.3
IL21R NM_021798.3
IL2RA NM_000417.2
IL2RG NM_000206.2
IL36RN NM_012275.2
ITCH NM_031483.6
ITGB2 NM_000211.4
ITK NM_005546.3
LIG4 NM_002312.3
LPIN2 NM_014646.2
LRBA NM_006726.4
LYST NM_000081.3
MAGT1 NM_032121.5
MEFV NM_000243.2
MVK NM_000431.3
NCF2 NM_000433.3
NCF4 NM_013416.3
NFAT5 NM_138714.3
NFKB2 NM_001077494.3
NFKBIA NM_020529.2
NLRC4 NM_021209.4
NLRP12 NM_144687.3
NLRP3 NM_004895.4
NOD2 NM_022162.2
ORAI1 NM_032790.3
PIK3CD NM_005026.3
PIK3R1 NM_181523.2; NM_181504.3
PLCG2 NM_002661.4
PNP NM_000270.3
PRF1 NM_001083116.1
PRKCD NM_006254.3
PSMB8 NM_148919.3
PSTPIP1 NM_003978.3
RAB27A NM_004580.4
RAC2 NM_002872.4
RAG1 NM_000448.2
RAG2 NM_000536.3
RBCK1 NM_031229.3
RFX5 NM_000449.3
RFXANK NM_003721.3
RFXAP NM_000538.3
RMRP NR_003051.3
RNASEH2A NM_006397.2
RNASEH2B NM_024570.3
RNASEH2C NM_032193.3
RTEL1 NM_032957.4; NM_001283009.1
SAMHD1 NM_015474.3
SH2D1A NM_002351.4
SH3BP2 NM_003023.4
SLC29A3 NM_018344.5
SLC37A4 NM_001164277.1
SLC7A7 NM_001126106.2
STAT1 NM_007315.3
STAT3 NM_139276.2
STAT5B NM_012448.3
STIM1 NM_003156.3
STX11 NM_003764.3
STXBP2 NM_006949.3; NM_001272034.1
TBX1 NM_080647.1
TMEM173 NM_198282.3
TNFRSF13B NM_012452.2
TNFRSF13C NM_052945.3
TNFRSF1A NM_001065.3
TNFSF12 NM_003809.2
TPP2 NM_003291.2
TREX1 NM_033629.4; NM_016381.4
TRNT1 NM_182916.2
TTC7A NM_020458.3
UNC13D NM_199242.2
UNG NM_080911.2
WAS NM_000377.2
XIAP NM_001167.3
ZAP70 NM_001079.3