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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.
Order test
Primary panel (46 genes)
Customized gene selection (0 included, 0 excluded)
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 (1 gene)
Customized gene selection (0 included, 0 excluded)
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
Clinical information
Disorders tested
| 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 |
Clinical description
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.
Clinical sensitivity
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
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.
Penetrance
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%.
Prevalence/Incidence
The monogenic IBDs are very rare, with a prevalence of 1 in 100,000 or less.
References
- 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
- 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
- Glocker, EO, et al. Infant colitis--it's in the genes. Lancet. 2010; 376(9748):1272. PMID: 20934598
- 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
- 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
- Uhlig, HH, et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology. 2014; 147(5):990-1007.e3. PMID: 25058236
- 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
- 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
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 |
Resources
Patient resources
Patient guide: Genetic testing simplifiedReferences
- Glocker, EO, et al. Infant colitis--it's in the genes. Lancet. 2010; 376(9748):1272. PMID: 20934598
- 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
- 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
- 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
- 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
- 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
- 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
- Uhlig, HH, et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology. 2014; 147(5):990-1007.e3. PMID: 25058236
