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  • Test code: 08122
  • Turnaround time:
    10–21 calendar days (14 days on average)
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    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
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  1. Test Catalog
  2. Invitae Monogenic Inflammatory Bowel Disease Panel

Invitae Monogenic Inflammatory Bowel Disease Panel

Test description

The Invitae Monogenic Inflammatory Bowel Disease Panel analyzes 47 genes that are associated with primary immunodeficiencies that lead to primarily pediatric onset inflammatory bowel disease (IBD). 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.

Genes tested

Primary panel

ADA ADAM17 AICDA BTK CD3G CD40LG CTLA4 CYBA CYBB DCLRE1C DKC1 DOCK8 FOXP3 G6PC3 ICOS IL10 IL10RA IL10RB IL21 IL2RA IL2RG ITGB2 LIG4 LRBA MEFV MVK NCF2 NCF4 NFAT5 NLRC4 PIK3CD PIK3R1 PLCG2 RAG1 RAG2 RTEL1 SH2D1A SLC37A4 STAT1 STAT3 STIM1 STXBP2 TTC7A WAS XIAP ZAP70

Add-on Increased risk alleles in NOD2 associated with Crohn’s disease

NOD2

Several common variants in NOD2 have been associated with an increased risk of Crohn’s disease. These variants are present in 1-3% of the population and are associated with approximately a 2- to 9-fold increased risk of Crohn’s disease (PMID: 21548950, 15024686, 18489434, 15571588). This gene can be included at no additional charge.

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Primary panel (46 genes)

ADA ADAM17 AICDA BTK CD3G CD40LG CTLA4 CYBA CYBB DCLRE1C DKC1 DOCK8 FOXP3 G6PC3 ICOS IL10 IL10RA IL10RB IL21 IL2RA IL2RG ITGB2 LIG4 LRBA MEFV MVK NCF2 NCF4 NFAT5 NLRC4 PIK3CD PIK3R1 PLCG2 RAG1 RAG2 RTEL1 SH2D1A SLC37A4 STAT1 STAT3 STIM1 STXBP2 TTC7A WAS XIAP ZAP70

Panel details and technical assay limitations
Add-on Increased risk alleles in NOD2 associated with Crohn’s disease (1 gene)

Several common variants in NOD2 have been associated with an increased risk of Crohn’s disease. These variants are present in 1-3% of the population and are associated with approximately a 2- to 9-fold increased risk of Crohn’s disease (PMID: 21548950, 15024686, 18489434, 15571588). This gene can be included at no additional charge.

NOD2

Panel details and technical assay limitations

Clinical information




Gene Disorder Protein name Protein symbol
ADA Adenosine deaminase (ADA) deficiency adenosine deaminase ADA
ADAM17 ADAM17 deletion tumor necrosis factor-alpha converting enzyme TACE
AICDA AID deficiency activation-induced cytidine deaminase AID
BTK BTK deficiency Bruton agammaglobulinemia tyrosine kinase BTK
CD3G CD3γ deficiency CD3-gamma CD3-gamma
CD40LG CD40 ligand deficiency CD40 ligand CD40LG
CTLA4 CTLA4 deficiency (ALPSV) Cytotoxic T Lymphocyte antigen 4 CTLA4
CYBA Autosomal recessive CGD 22kD-phagocyte oxidase p22-phox
CYBB X-linked 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
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
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
IL21 IL-21 deficiency IL-21 deficiency IL-21
IL2RA CD25 deficiency CD25 CD25
IL2RG γc deficiency, XSCID interleukin receptor common gamma chain gamma-c
ITGB2 Leukocyte adhesion deficiency type 1 integrin beta 2 ITGB2
LIG4 DNA ligase IV deficiency DNA ligase IV LIG4
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 NLR family, CARD containing 4 NLRC4
autoinflammatory syndrome 4
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 phospholipase C gamma 2 PLCG2
autoinflammatory syndrome 3, APLAID (autoinflammation
and PLCγ2 associated antibody deficiency and immune dysregulation)
RAG1 RAG 1 deficiency recombinase activating gene 1 RAG1
RAG2 RAG 2 deficiency recombinase activating gene 2 RAG2
RTEL1 AR-DKC due to regulator of telomere elongation (RTEL1) deficiency regulator of telomere elongation helicase 1 RTEL1
SH2D1A SH2D1A deficiency (XLP1) SH2 domain protein 1A SH2D1A
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
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

Monogenic inflammatory bowel disease (IBD) is caused most often by primary immunodeficiencies that result from inappropriate adaptive or innate immune response to intestinal flora or defects in the intestinal mucosal barrier. Monogenic IBD can be characterized as Crohn’s disease, ulcerative colitis, or in some cases, particularly with very early onset, unspecified IBD. The monogenic IBDs can be sub-typed by age of onset: neonatal onset IBD presents within the first 28 days of life, infantile onset IBD presents between 28 days and 2 years of life, very early onset IBD presents from 2 years to less than 6 years of age, and early onset IBD presents from 6 years to less than 10 years of age. Many presenting symptoms are typical of IBD including loose stools, diarrhea, severe colitis with deep ulcerations and granuloma, weight loss and related growth restriction. Additional features can include perianal disease (abscesses, fissures and fistula), dermatologic abnormalities (recurrent folliculitis, eczematous skin lesions), autoimmunity, and in some disorders increased risk for neoplasms. The pediatric onset of presentation distinguish the IBD from more typical forms of IBD. Individuals often do not respond well to conventional IBD therapies and emerging studies show a potential role for hematopoietic stem-cell transplantation in treatment.

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

Inheritance of the monogenic IBD depend on the underlying genetic etiology. Monogenic IBD can be inherited in an autosomal recessive, autosomal dominant, and X-linked manner.

The penetrance for IBD due to pathogenic variants in IL10, IL10RA, IL10RB, and FOXP3 is at or near 100%. IBD due to pathogenic variants in XIAP, any of the CGD genes, and MVK shows incomplete penetrance that ranges from 10% to 30%. The penetrance of IBD due to pathogenic variants in other genes in this panel is unknown but estimated to be above 5%.

The monogenic IBDs are very rare, with a prevalence of 1 in 100,000 or less.

  1. Pigneur, B, et al. Phenotypic characterization of very early-onset IBD due to mutations in the IL10, IL10 receptor alpha or beta gene: a survey of the Genius Working Group. Inflamm. Bowel Dis. 2013; 19(13):2820-8. PMID: 24216686
  2. Kotlarz, D, et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology. 2012; 143(2):347-55. PMID: 22549091
  3. Glocker, EO, et al. Infant colitis--it's in the genes. Lancet. 2010; 376(9748):1272. PMID: 20934598
  4. Glocker, EO, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 2009; 361(21):2033-45. PMID: 19890111
  5. Picard, C, et al. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J. Clin. Immunol. 2015; 35(8):696-726. PMID: 26482257
  6. Uhlig, HH, et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology. 2014; 147(5):990-1007.e3. PMID: 25058236
  7. Kammermeier, J, et al. Phenotypic and genotypic characterisation of inflammatory bowel disease presenting before the age of 2 years. J Crohns Colitis. 2016; :None. PMID: 27302973
  8. Uhlig, HH, Schwerd, T. From Genes to Mechanisms: The Expanding Spectrum of Monogenic Disorders Associated with Inflammatory Bowel Disease. Inflamm. Bowel Dis. 2016; 22(1):202-12. PMID: 26512716

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
ADA NM_000022.2
ADAM17 NM_003183.5
AICDA NM_020661.2
BTK NM_000061.2
CD3G NM_000073.2
CD40LG NM_000074.2
CTLA4 NM_005214.4
CYBA NM_000101.3
CYBB NM_000397.3
DCLRE1C NM_001033855.2
DKC1 NM_001363.4
DOCK8 NM_203447.3
FOXP3 NM_014009.3
G6PC3 NM_138387.3
ICOS NM_012092.3
IL10 NM_000572.2
IL10RA NM_001558.3
IL10RB NM_000628.4
IL21 NM_021803.3
IL2RA NM_000417.2
IL2RG NM_000206.2
ITGB2 NM_000211.4
LIG4 NM_002312.3
LRBA NM_006726.4
MEFV NM_000243.2
MVK NM_000431.3
NCF2 NM_000433.3
NCF4 NM_013416.3
NFAT5 NM_138714.3
NLRC4 NM_021209.4
NOD2 NM_022162.2
PIK3CD NM_005026.3
PIK3R1 NM_181523.2
PLCG2 NM_002661.4
RAG1 NM_000448.2
RAG2 NM_000536.3
RTEL1 NM_001283009.1
SH2D1A NM_002351.4
SLC37A4 NM_001164277.1
STAT1 NM_007315.3
STAT3 NM_139276.2
STIM1 NM_003156.3
STXBP2 NM_006949.3
TTC7A NM_020458.3
WAS NM_000377.2
XIAP NM_001167.3
ZAP70 NM_001079.3

Clinical resources
Immunology gene list Invitae brochure
Patient resources
Patient guide: Genetic testing simplified
Test information
Forms page Specimen requirements page

References

  1. Glocker, EO, et al. Infant colitis--it's in the genes. Lancet. 2010; 376(9748):1272. PMID: 20934598
  2. Glocker, EO, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 2009; 361(21):2033-45. PMID: 19890111
  3. Kammermeier, J, et al. Phenotypic and genotypic characterisation of inflammatory bowel disease presenting before the age of 2 years. J Crohns Colitis. 2016; :None. PMID: 27302973
  4. Kotlarz, D, et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology. 2012; 143(2):347-55. PMID: 22549091
  5. Picard, C, et al. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J. Clin. Immunol. 2015; 35(8):696-726. PMID: 26482257
  6. Pigneur, B, et al. Phenotypic characterization of very early-onset IBD due to mutations in the IL10, IL10 receptor alpha or beta gene: a survey of the Genius Working Group. Inflamm. Bowel Dis. 2013; 19(13):2820-8. PMID: 24216686
  7. Uhlig, HH, Schwerd, T. From Genes to Mechanisms: The Expanding Spectrum of Monogenic Disorders Associated with Inflammatory Bowel Disease. Inflamm. Bowel Dis. 2016; 22(1):202-12. PMID: 26512716
  8. Uhlig, HH, et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology. 2014; 147(5):990-1007.e3. PMID: 25058236

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