Test Id : EOIBD

For skin biopsy or cultured fibroblast specimens, fibroblast culture will be performed at an additional charge. If viable cells are not obtained, the client will be notified.

For more information see Inflammatory Bowel Disease Diagnostic Testing Algorithm.

Targeted testing for familial variants (also called site-specific or known variants testing) is available for the genes on this panel. See FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about this testing option, call 800-533-1710.

Specimen preferred to arrive within 96 hours of collection.

Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

Submit only 1 of the following specimens:

Specimen Type: Whole blood

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send whole blood specimen in original tube. Do not aliquot.

Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated

Specimen Type: Skin biopsy

Supplies: Fibroblast Biopsy Transport Media (T115)

Container/Tube: Sterile container with any standard cell culture media (eg, minimal essential media, RPMI 1640). The solution should be supplemented with 1% penicillin and streptomycin.

Specimen Volume: 4-mm punch

Specimen Stability Information: Refrigerated (preferred)/Ambient

Additional Information: A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.

Specimen Type: Cultured fibroblasts

Container/Tube: T-25 flask

Specimen Volume: 2 Flasks

Collection Instructions: Submit confluent cultured fibroblast cells from a skin biopsy from another laboratory. Cultured cells from a prenatal specimen will not be accepted.

Specimen Stability Information: Ambient (preferred)/Refrigerated (<24 hours)

Additional Information: A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.

• Informed Consent for Genetic Testing
• Informed Consent for Genetic Testing (Spanish)
• Early Onset Inflammatory Bowel Disease Patient Information
• Targeted Genes and Methodology Details for Early Onset Monogenic Inflammatory Bowel Disease (IBD) Gene Panel
• Inflammatory Bowel Disease Diagnostic Testing Algorithm

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing (Spanish) (T826)

2. Early Onset Inflammatory Bowel Disease Patient Information

3. If not ordering electronically, complete, print, and send a Gastroenterology and Hepatology Test Request (T728) with the specimen.

Blood: 1 mL

Skin biopsy or cultured fibroblasts: See Specimen Required

Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of an inherited inflammatory bowel disorder

Establishing a diagnosis of a monogenic early onset inflammatory bowel disease, allowing for appropriate management and surveillance for disease features based on the gene and/or variant involved

Identifying variants within genes known to be associated with monogenic early onset inflammatory bowel disease, allowing for predictive testing of at-risk family members

This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in 107 genes associated with monogenic early onset inflammatory bowel disease: ADA, ADAM17, AICDA, AIRE, ALPI, ANKZF1, ARPC1B, ASAH1, BACH2, BTK, CARMIL2, CASP8, CD3G, CD40LG, CD55, COL7A1, CTLA4, CYBA, CYBB, CYBC1, DCLRE1C, DEF6, DGAT1, DKC1, DOCK8, DUOX2, EPCAM, FCHO1, FERMT1, FOXP3, G6PC(G6PC1), G6PC3, GUCY2C, HPS1, HPS3, HPS4, HPS6, ICOS, IFIH1, IKBKG, IL10, IL10RA, IL10RB, IL21, IL21R, IL2RA, IL2RB, IL2RG, IL7R, ITCH, ITGB2, JAK1, LCT, LIG4, LRBA, MALT1, MEFV, MVK, MYO5B, NCF2, NCF4, NEUROG3, NFKBIA, NLRC4, PAX1, PCSK1, PIK3CD, PIK3R1, PLCG2, PLVAP, POLA1, RAG1, RAG2, RIPK1, RTEL1, SH2D1A, SI, SKIV2L, SLC10A2, SLC26A3, SLC37A4, SLC39A4, SLC51B, SLC5A1, SLC9A3, SPINT2, STAT1, STAT3, STAT5B, STIM1, STX3, STXBP2, TGFB1, TGFBR1, TGFBR2, TLR3, TNFAIP3, TRIM22, TRNT1, TTC37, TTC7A, UNC45A, WAS, WIPF1, XIAP, ZAP70, and ZBTB24. See Targeted Genes and Methodology Details for Early Onset Monogenic Inflammatory Bowel Disease (IBD) Gene Panel for details regarding the targeted gene regions evaluated by this test.

Identification of a disease-causing variant may assist with diagnosis, prognosis, clinical management, recurrence risk assessment, familial screening, and genetic counseling for monogenic early onset inflammatory bowel disease.

For skin biopsy or cultured fibroblast specimens, fibroblast culture will be performed at an additional charge. If viable cells are not obtained, the client will be notified.

For more information see Inflammatory Bowel Disease Diagnostic Testing Algorithm.

Inflammatory bowel disease (IBD) is a term encompassing numerous disorders featuring chronic intestinal inflammation. These conditions are typically classified as either Crohn disease or ulcerative colitis based on clinical features, colonoscopy findings, histologic changes, and the anatomical distribution of disease. However, some cases are not readily classified or may have overlapping features and are classified as IBD-unspecified (IBD-U). The incidence of IBD has rapidly increased in children and adults over the past few decades. Common symptoms include diarrhea, abdominal pain, fatigue, and failure to thrive or unintentional weight loss.

IBD is caused by a combination of dysregulated immune response, microbial dysbiosis, and environmental triggers and occurs in individuals with genetic susceptibility. Most IBD is thought to be either polygenic or multifactorial. However, in rare cases, IBD or IBD-like intestinal inflammation can be attributed to disease-causing variants in a single gene (ie, monogenic inheritance) that result in a highly penetrant condition that presents early in life. Many monogenic forms of IBD are disorders of immune deficiency or dysregulation. Genes associated with IBD continue to be identified with advances in sequencing technology. However, 70% to 80% of patients have IBD without a known genetic etiology.

While the peak age of onset of IBD is between the ages of 20 and 40 years, the incidence of IBD in pediatric patients is increasing. When IBD presents in children younger than 6 years old, it is described as very early onset IBD (VEO-IBD). IBD that presents in children younger than 2 years old is described as infantile-onset IBD. VEO-IBD differs from IBD in older patients in that it is more likely to be IBD-U and have a monogenic cause, particularly among those with infantile-onset IBD.

Conditions associated with VEO-IBD can be grouped into the following broad, sometimes overlapping categories: disorders of general immune dysregulation (eg,. IL-10 signaling defects, IPEX syndrome, STAT3 gain-of-function); T- and B-cell defects (eg,. LRBA deficiency, CTLA4 deficiency, Wiskott Aldrich syndrome, severe combined immunodeficiency [SCID]/Omenn syndrome); phagocytic defects (eg,. chronic granulomatous disease); hyper- or auto-inflammatory disorders (eg,. familial Mediterranean fever, familial hemophagocytic lymphohistiocytosis); epithelial barrier dysfunction (eg, TTC7A deficiency, nuclear factor kappa B essential modulator [NEMO] deficiency); and syndromic conditions (eg, trichohepatoenteric syndrome, CHAPLE [CD55 deficiency with hyper-activation of complement, angiopathic thrombosis, and severe protein-losing enteropathy] syndrome).

Previous reports indicate patients with a monogenic form of IBD may not respond as well to conventional treatment modalities. Identification of the genetic cause of disease in these individuals is important as it may change their treatment plan. Depending on the genetic cause, targeted therapies or allogeneic hematopoietic stem cell transplantation may be beneficial. Therefore, early diagnosis and identification of the specific underlying genetic alteration is important in order to inform treatment, such as medical therapy, surgery, and stem cell transplant and to reduce the high morbidity and mortality associated with these conditions.

Individuals with polygenic or monogenic IBD may have other family members affected with IBD. A family history of IBD is more common among those with VEO-IBD. If a monogenic cause is identified in an individual, family members may be tested for the genetic variant to assess their risk of developing IBD or to guide therapy for those who are affected.

An interpretive report will be provided.

All detected variants are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Clinical Correlations:

Test results should be interpreted in the 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 clinically significant family history, it is often useful to first test an affected family member. Detection of a reportable variant in an affected family member would allow for more informative testing of at-risk individuals.

To discuss the availability of additional testing options or for assistance in the interpretation of these results, contact Mayo Clinic Laboratories genetic counselors at 800-533-1710.

Technical Limitations:

Next-generation sequencing may not detect all types of genomic variants. In rare cases, false-negative or false-positive results may occur. The depth of coverage may be variable for some target regions; assay performance below the minimum acceptable criteria or for failed regions will be noted. Given these limitations, negative results do not rule out the diagnosis of a genetic disorder. If a specific clinical disorder is suspected, evaluation by alternative methods can be considered.

There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. Confirmation of select reportable variants will be performed by alternate methodologies based on internal laboratory criteria.

This test is validated to detect 95% of deletions up to 75 base pairs (bp) and insertions up to 47 bp. Deletions-insertions (delins) of 40 or more bp, including mobile element insertions, may be less reliably detected than smaller delins.

Deletion/Duplication Analysis:

This analysis targets single and multi-exon deletions/duplications; however, in some instances, single exon resolution cannot be achieved due to isolated reduction in sequence coverage or inherent genomic complexity. Balanced structural rearrangements (such as translocations and inversions) may not be detected.

This test is not designed to detect low levels of mosaicism or to differentiate between somatic and germline variants. If there is a possibility that any detected variant is somatic, additional testing may be necessary to clarify the significance of results.

Genes may be added or removed based on updated clinical relevance. For detailed information regarding gene specific performance and technical limitations, see Method Description or contact a laboratory genetic counselor.

If the patient has had an allogeneic hematopoietic stem cell transplant or a nonleukoreduced blood transfusion, results may be inaccurate due to the presence of donor DNA. Call Mayo Clinic Laboratories for instructions for testing patients who have received a bone marrow transplant.

Reclassification of Variants:

Currently, it is not standard practice for the laboratory to systematically review previously classified variants on a regular basis. The laboratory encourages health care providers to contact the laboratory at any time to learn how the classification of a particular variant may have changed over time. Due to broadening genetic knowledge, it is possible that the laboratory may discover new information of relevance to the patient. Should that occur, the laboratory may issue an amended report.

Variant Evaluation:

Evaluation and categorization of variants are performed using published American College of Medical Genetics and Genomics and the Association for Molecular Pathology recommendations as a guideline. (1) Other gene-specific guidelines may also be considered. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. Variants classified as benign or likely benign are not reported.

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 periodic updates to these tools may cause predictions to change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgement.

Rarely, incidental or secondary findings may implicate another predisposition or presence of active disease. These findings will be carefully reviewed to determine whether they will be reported.

1. Uhlig HH, Schwerd T, Koletzko S, et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology. 2014;147(5):990-1007

2. 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):202-212

3. Kelsen JR, Baldassano RN, Artis D, Sonnenberg GF. Maintaining intestinal health: the genetics and immunology of very early-onset inflammatory bowel disease. Cell Mol Gastroenterol Hepatol. 20151;1(5):462-476

4. Ouahed J, Spencer E, Kotlarz D, et al. Very early onset inflammatory bowel disease: A clinical approach with a focus on the role genetics and underlying immune deficiencies. Inflamm Bowel Dis. 2020;26(6):820-842

5. 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;17(5)405-24

Next-generation sequencing (NGS) and/or Sanger sequencing is performed to test for the presence of variants in coding regions and intron/exon boundaries of the genes analyzed, as well as some other regions that have known disease-causing variants. The human genome reference GRCh37/hg19 build was used for sequence read alignment. At least 99% of the bases are covered at a read depth over 30X. Sensitivity is estimated at above 99% for single nucleotide variants, above 94% for deletions/insertions (delins) less than 40 base pairs (bp), above 95% for deletions up to 75 bp and insertions up to 47 bp. NGS and/or a polymerase chain reaction-based quantitative method is performed to test for the presence of deletions and duplications in the genes analyzed.

There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. See Targeted Genes and Methodology Details for Early Onset Monogenic Inflammatory Bowel Disease (IBD) Gene Panel for details regarding the targeted gene regions identified by this test.(Unpublished Mayo method) (Unpublished Mayo method)

Genes analyzed: ADA, ADAM17, AICDA, AIRE, ALPI, ANKZF1, ARPC1B, ASAH1, BACH2, BTK, CARMIL2, CASP8, CD3G, CD40LG, CD55, COL7A1, CTLA4, CYBA, CYBB, CYBC1, DCLRE1C, DEF6, DGAT1, DKC1, DOCK8, DUOX2, EPCAM, FCHO1, FERMT1, FOXP3, G6PC(G6PC1), G6PC3, GUCY2C, HPS1, HPS3, HPS4, HPS6, ICOS, IFIH1, IKBKG, IL10, IL10RA, IL10RB, IL21, IL21R, IL2RA, IL2RB, IL2RG, IL7R, ITCH, ITGB2, JAK1, LCT, LIG4, LRBA, MALT1, MEFV, MVK, MYO5B, NCF2, NCF4, NEUROG3, NFKBIA, NLRC4, PAX1, PCSK1, PIK3CD, PIK3R1, PLCG2, PLVAP, POLA1, RAG1, RAG2, RIPK1, RTEL1, SH2D1A, SI, SKIV2L, SLC10A2, SLC26A3, SLC37A4, SLC39A4, SLC51B, SLC5A1, SLC9A3, SPINT2, STAT1, STAT3, STAT5B, STIM1, STX3, STXBP2, TGFB1, TGFBR1, TGFBR2, TLR3, TNFAIP3, TRIM22, TRNT1, TTC37, TTC7A, UNC45A, WAS, WIPF1, XIAP, ZAP70, and ZBTB24

Varies

• Authorized users can sign in to Test Prices for detailed fee information.
• Clients without access to Test Prices can contact Customer Service 24 hours a day, seven days a week.
• Prospective clients should contact their account representative. For assistance, contact Customer Service.

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.

81443

88233- Tissue culture, skin, solid tissue biopsy (if appropriate)

88240- Cryopreservation (if appropriate)