Sunflower Health Plan Concert Genetic Testing: Gastroenterologic Disorders non cancerous (PDF) Form

Genetic Testing: Gastroenterologic Disorders (non-cancerous) V2.2023 Date of Last Revision: 3/1/2023 CONCERT GENETIC TESTING: GASTROENTEROLOGIC DISORDERS (NON-CANCEROUS) See Important Reminder at the end of this policy for important regulatory and legal information. OVERVIEW Genetic testing for gastroenterologic (non-cancerous) disorders may be used to confirm a diagnosis in a patient who has signs and/or symptoms of a specific gastroenterologic disorder. Confirming the diagnosis may alter aspects of management and may eliminate the need for further diagnostic workup. This document addresses genetic testing for common gastroenterologic (non-cancerous) conditions. POLICY REFERENCE TABLE Below is a list of higher volume tests and the associated laboratories for each coverage criteria section. This list is not all inclusive. This clinical policy references Current Procedural Terminology (CPT®). CPT® is a registered trademark of the American Medical Association. All CPT codes and descriptions are copyrighted 2022, American Medical Association. All rights reserved. CPT codes and CPT descriptions are from the current manuals and those included herein are not intended to be all-inclusive and are included for informational purposes only. Codes referenced in this clinical policy are for informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage. Providers should reference the most up-to-date sources of professional coding guidance prior to the submission of claims for reimbursement of covered services. Coverage Criteria Sections Example Tests (Labs) Common CPT Codes Common ICD Codes Ref 1 Genetic Testing: Gastroenterologic Disorders (non-cancerous) Genetic Testing: Gastroenterologic Disorders (non-cancerous) V2.2023 V2.2023 Date of Last Revision: 3/1/2023 Date of Last Revision: 3/1/2023 Known Familial Variant Analysis for Gastroenterologic Disorders Known Familial Variant Analysis for Gastroenterologic Disorders Known Familial Variant Analysis for Gastroenterologic Disorders Celiac Disease Celiac Disease HLA-DQ Variant HLA-DQ Variant Analysis Analysis Targeted Mutation Analysis for a Known Familial Variant 81403 81403 HLA DQ Association (LabCorp) HLA DQ Association (LabCorp) HLA DRB1,3,4,5,DQB1, Low HLA DRB1,3,4,5,DQB1, Low Resolution (Quest Diagnostics) Resolution (Quest Diagnostics) HLA Typing for Celiac Disease (Quest HLA Typing for Celiac Disease (Quest Diagnostics) Diagnostics) 81370, 81375, 81370, 81375, 81376, 81377, 81376, 81377, 81382, 81383 81382, 81383 K90.0, R10.0 K90.0, R10.0 through through R10.13, R10.3 R10.13, R10.3 through through R10.829, R10.829, R10.84 R10.84 through R10.9 through R10.9 16 16 4, 5, 6 4, 5, 6 Hereditary Hemochromatosis Hereditary Hemochromatosis HFE Sequencing HFE Sequencing and/or and/or Deletion/Duplication Deletion/Duplication Analysis Analysis Hereditary Hemochromatosis via the Hereditary Hemochromatosis via the HFE Gene (PreventionGenetics) HFE Gene (PreventionGenetics) Hereditary Hemochromatosis DNA Hereditary Hemochromatosis DNA Mutation Analysis (Quest Diagnostics) Mutation Analysis (Quest Diagnostics) 81479 81479 81256 81256 1, 7 1, 7 E83.110, E83.110, E83.118, E83.118, E83.119, E83.119, R79.0, E83.19, R79.0, E83.19, R16.0 R16.0 Lactase Insufficiency Lactase Insufficiency MCM6 Targeted MCM6 Targeted Variant Analysis Variant Analysis Lactose intolerance (polymorphisms- Lactose intolerance (polymorphisms- 13910C>T; c.1917+326C>T and 13910C>T; c.1917+326C>T and 22018G>A; 1362+117G>A on MCM6 22018G>A; 1362+117G>A on MCM6 gene) (CGC Genetics) gene) (CGC Genetics) Hereditary Pancreatitis Hereditary Pancreatitis 81479 81479 E73.1 E73.1 14, 15 14, 15 Hereditary Hereditary Pancreatitis Multigene Pancreatitis Multigene Panel Panel Hereditary Pancreatitis Panel (GeneDx) 81222, 81223, Hereditary Pancreatitis Panel (GeneDx) 81222, 81223, 81404, 81405, 81404, 81405, 81479 81479 K85.0 through K85.0 through K85.9, K86.1, K85.9, K86.1, Z83.79 Z83.79 2, 3 2, 3 Inflammatory Bowel Disease Inflammatory Bowel Disease Inflammatory Bowel Inflammatory Bowel Disease / Crohn’s Disease / Crohn’s Prometheus IBD sgi Diagnostic Prometheus IBD sgi Diagnostic (Prometheus Laboratories) (Prometheus Laboratories) 81479, 82397, 81479, 82397, 83520, 86140, 83520, 86140, 88346, 88350 88346, 88350 K50 through K50 through K52 K52 8 8 2 2 Genetic Testing: Gastroenterologic Disorders (non-cancerous) V2.2023 Date of Last Revision: 3/1/2023 Disease Diagnostic Algorithmic Tests IBD sgi Diagnostic (Children’s Hospital of Philadelphia-Division of Genomic Diagnostics) 83520, 82397, 86140,88342, 81479 Inflammatory Bowel Disease / Crohn’s Disease Prognostic Algorithmic Tests Hereditary Inflammatory Bowel Disease / Crohn’s Disease Panel Tests PredictSURE IBD (KSL Diagnostics) 0203U K50 through K52 9 9 Crohn’s Disease Prognostic Panel (ARUP Laboratories) 83516, 86671 Prometheus Crohn’s Prognostic (Prometheus Laboratories) 81401, 83520, 88346, 88350 Monogenic Inflammatory Bowel Disease Panel-Primary Genes (Invitae) 81479 K50 through K52 10, 11, 10, 11, 12 12 Very Early Onset Inflammatory Bowel Genomic Panel (Children’s Hospital of Philadelphia-Division of Genomic Diagnostics) Test Specific Not Covered Gastroenterologic Disorders Tests Test Specific Not Covered Gastroenterologic Disorders Tests ASH FibroSURE (LabCorp) 0002M K22.7, K74, K75, 13 13 NASH FibroSURE (LabCorp) EsoGuard (Lucid Diagnostics) 0003M 0114U OTHER RELATED POLICIES This policy document provides coverage criteria for Genetic Testing for Gastroenterologic Conditions (Non-Cancerous). Please refer to: ● Genetic Testing: Hereditary Cancer Susceptibility Syndromes for coverage criteria related to germline testing for hereditary cancer syndromes, including Lynch/HNPCC syndrome. ● Genetic Testing: Prenatal and Preconception Carrier Screening for coverage criteria related to carrier screening in the prenatal, preimplantation, and preconception setting. 3 Genetic Testing: Gastroenterologic Disorders (non-cancerous) V2.2023 Date of Last Revision: 3/1/2023 ● Genetic Testing: Prenatal Diagnosis (via amniocentesis, CVS, or PUBS) and Pregnancy Loss for coverage related to prenatal and pregnancy loss diagnostic genetic testing for tests intended to diagnose genetic conditions following amniocentesis, chorionic villus sampling or pregnancy loss. ● Genetic Testing: Multisystem Inherited Disorders, Intellectual Disability, and Developmental Delay for coverage criteria related to diagnostic genetic testing for conditions affecting multiple organ systems. ● Genetic Testing: Metabolic, Endocrine, and Mitochondrial Disorders for coverage criteria related to genetic testing for MTHFR. ● Genetic Testing: General Approach to Genetic Testing for coverage criteria related to genetic testing for any non-cancerous GI disorders that is not specifically discussed in this or another non-general policy. CRITERIA It is the policy of health plans affiliated with Centene Corporation® that the specific genetic testing noted below is medically necessary when meeting the related criteria: KNOWN FAMILIAL VARIANT ANALYSIS FOR GASTROENTEROLOGIC DISORDERS I. Targeted mutation analysis for a known familial variant (81403) for a gastroenterologic disorder is considered medically necessary when: A. The member/enrollee has a close relative with a known pathogenic or likely pathogenic variant causing the condition. II. Targeted mutation analysis for a known familial variant (81403) for a gastroenterologic disorder is considered investigational for all other indications. back to top 4 Genetic Testing: Gastroenterologic Disorders (non-cancerous) V2.2023 Date of Last Revision: 3/1/2023 CELIAC DISEASE HLA-DQ Genotyping Analysis I. HLA-DQ2 and HLA-DQ8 variant analysis (81370, 81375, 81376, 81377, 81382, 81383) to rule out celiac disease is considered medically necessary when: A. The member/enrollee meets one of the following: 1. The member/enrollee has equivocal small-bowel histological finding in seronegative patients, OR 2. The member/enrollee is on a gluten-free diet AND in whom no testing for CD was done before gluten-free diet, OR 3. The member/enrollee has discrepant celiac-specific serology and histology, OR 4. Patients with suspicion of refractory CD where the original diagnosis of celiac remains in question. II. HLA-DQ2 and HLA-DQ8 variant analysis (81370, 81375, 81376, 81377, 81382, 81383) to rule out celiac disease is considered investigational for all other indications. back to top HEREDITARY HEMOCHROMATOSIS HFE Sequencing and/or Deletion/Duplication Analysis I. HFE sequencing and/or deletion/duplication analysis (81256, 81479) to establish a diagnosis of hereditary hemochromatosis is considered medically necessary when: A. The member/enrollee has abnormal serum iron indices, especially elevated serum transferrin-iron saturation and/or elevated serum ferritin concentration, indicating iron overload, OR B. The member/enrollee has a first-degree relative with a diagnosis of hereditary hemochromatosis, especially if the relative has Type I HH where the relative has two C282Y mutations (homozygous). 5 Genetic Testing: Gastroenterologic Disorders (non-cancerous) V2.2023 Date of Last Revision: 3/1/2023 II. HFE sequencing and/or deletion/duplication analysis (81256, 81479) to screen for hereditary hemochromatosis in the general population is considered investigational. III. HFE sequencing and/or deletion/duplication analysis (81256, 81479) to establish a diagnosis of hereditary hemochromatosis is considered investigational for all other indications. back to top LACTASE INSUFFICIENCY MCM6 Targeted Variant Analysis I. MCM6 variant analysis (81479) for the prediction of lactase insufficiency is considered investigational. back to top HEREDITARY PANCREATITIS Hereditary Pancreatitis Multigene Panel I. Hereditary pancreatitis multigene panel analysis (81222, 81223, 81404, 81405, 81479) to establish a diagnosis of hereditary pancreatitis is considered medically necessary when: A. The member/enrollee has personal history of pancreatitis, AND B. The member/enrollee meets at least one of the following; 1. The member/enrollee has an unexplained episode of acute pancreatitis in childhood (18 years or younger), OR 2. The member/enrollee has recurrent (two or more separate, documented) acute attacks of pancreatitis for which there is no explanation (anatomical anomalies, ampullary or main pancreatic strictures, trauma, viral infection, gallstones, alcohol, drugs, hyperlipidemia, etc.), OR 3. Chronic pancreatitis of unknown cause, particularly with onset before age 35 years without a history of heavy alcohol use, OR 6 Genetic Testing: Gastroenterologic Disorders (non-cancerous) V2.2023 Date of Last Revision: 3/1/2023 4. A history of at least one close relative with recurrent acute pancreatitis, chronic pancreatitis of unknown cause, or childhood pancreatitis of unknown cause, AND C. The panel includes, at a minimum, the following genes: PRSS1, SPINK, CFTR and CTRC. II. Hereditary pancreatitis multigene panel analysis (81222, 81223, 81404, 81405, 81479) to establish a diagnosis of hereditary pancreatitis is considered investigational for all other indications. back to top INFLAMMATORY BOWEL DISEASE Inflammatory Bowel Disease / Crohn’s Disease Diagnostic Algorithmic Tests I. Inflammatory bowel disease diagnostic algorithmic tests (81479, 82397, 83520, 86140, 88342, 88346, 88350) are considered investigational. back to top Inflammatory Bowel Disease / Crohn’s Disease Prognostic Algorithmic Tests I. Inflammatory bowel disease prognostic algorithmic tests (0203U, 81401, 83516, 83520, 86671, 88346, 88350) are considered investigational. back to top Hereditary Inflammatory Bowel Disease / Crohn’s Disease Panel Tests I. Genetic testing for inflammatory bowel disease (81479), including Crohn’s disease, via a multigene panel is considered medically necessary when: A. The member/enrollee has very early onset of typical IBD symptoms before age 2 years, OR 7 Genetic Testing: Gastroenterologic Disorders (non-cancerous) V2.2023 Date of Last Revision: 3/1/2023 B. The member/enrollee is under the age of 18 with aggressive, refractory or unusual IBD presentation, OR C. The member/enrollee is under the age of 18 with IBD symptoms, and also has a family history of IBD or immunodeficiency. II. Genetic testing for inflammatory bowel disease (81479), including Crohn’s disease, via a multigene panel is considered investigational for all other indications. back to top TEST-SPECIFIC NOT COVERED GASTROENTEROLOGIC DISORDERS TESTS I. The use of these specific gastroenterologic disorders tests are considered investigational: A. ASH FibroSURE (0002M) B. NASH FibroSURE (0003M) C. EsoGuard (0114U) back to top NOTES AND DEFINITIONS 1. Close relatives include first, second, and third degree blood relatives on the same side of the family: a. First-degree relatives are parents, siblings, and children b. Second-degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren, and half siblings c. Third-degree relatives are great grandparents, great aunts, great uncles, great grandchildren, and first cousins 2. Typical inflammatory bowel disease (IBD) symptoms include diarrhea, abdominal pain, infections, and bleeding. 8 Genetic Testing: Gastroenterologic Disorders (non-cancerous) V2.2023 Date of Last Revision: 3/1/2023 3. Aggressive, refractory or unusual IBD presentation includes: a. Recurrent severe infections or atypical infections consistent with diagnostic criteria of a primary immunodeficiency, b. Hemophagocytic lymphohistiocytosis c. Autoimmune features in particular features of i. Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome ii. Malignancies or multiple intestinal atresias d. Unusual disease evolution e. Non-response to multiple IBD medications back to top BACKGROUND AND RATIONALE Known Familial Variant Analysis for Gastroenterologic Disorders Genetic Support Foundation The Genetic Support Foundation’s Genetics 101 information on inheritance patterns says the following about testing for familial pathogenic variants: Genetic testing for someone who may be at risk for an inherited disease is always easier if we know the specific genetic cause. Oftentimes, the best way to find the genetic cause is to start by testing someone in the family who is known or strongly suspected to have the disease. If their testing is positive, then we can say that we have found the familial pathogenic (harmful) variant. We can use this as a marker to test other members of the family to see who is also at risk. Celiac Disease - HLA-DQ Variant Analysis American College of Gastroenterology The guidelines from the American College of Gastroenterology (2013) addressing the diagnosis and management of celiac disease (CD) stated the following on human leukocyte antigen (HLA) gene testing: 9 Genetic Testing: Gastroenterologic Disorders (non-cancerous) V2.2023 Date of Last Revision: 3/1/2023 1. HLA-DQ2/DQ8 testing should not be used routinely in the initial diagnosis of CD [celiac disease] (Strong recommendation, moderate level of evidence). 2. HLA-DQ2/DQ8 genotyping testing should be used to effectively rule out the disease in selected clinical situations (Strong recommendation, moderate level of evidence). 3. Examples of such clinical situations include but are not limited to: a. Equivocal small-bowel histological finding (Marsh I-II) in seronegative patients b. Evaluation of patients on a gluten-free diet in whom no testing for CD was done before gluten-free diet c. Patients with discrepant celiac-specific serology and histology d. Patients with suspicion of refractory CD where the original diagnosis of celiac remains in question. (p. 9) The 2013 guidelines from the American College of Gastroenterology do not recommend routine testing of family members, because of the high likelihood (>80%) of these individuals encoding HLA susceptibility. (p. 3) American Gastroenterological Association Institute The American Gastroenterological Association Institute (2006) issued a position statement on the diagnosis and management of CD. Regarding serologic testing, the Institute concluded that, in the primary care setting, the transglutaminase immunoglobulin (Ig) A antibody test is the most efficient single serologic test for diagnosing CD. The guidelines indicated that the antiendomysial antibodies IgA test is more time-consuming and operator dependent than the tissue transglutaminase (tTG). If IgA deficiency is strongly suspected, testing with IgG anti endomysial antibody (EMA) and/or tTG IgG antibody test is recommended. If serologic test results are negative and CD is still strongly suspected, providers can test for the presence of the disease- associated HLA alleles and, if present, perform a small intestinal mucosal biopsy. Alternatively, if signs and symptoms suggest that small intestinal biopsy is appropriate, patients can proceed to biopsy without testing for HLA alleles. (p. 4) U.S. Preventive Services Task Force The US Preventive Service Task Form (2017) released guidelines on screening adults and children for CD. These guidelines reviewed the use of tTG IgA testing followed by an intestinal biopsy to screen asymptomatic patients. Genotype testing was not discussed. The overall 10 Genetic Testing: Gastroenterologic Disorders (non-cancerous) V2.2023 Date of Last Revision: 3/1/2023 conclusion of this review was that the current balance of evidence was insufficient to assess benefits and harms resulting from screening for CD. (p. 1252) Hereditary Hemochromatosis - HFE Sequencing and/or Deletion/Duplication Analysis American College of Gastroenterology (ACG) In 2019, practice guidelines from the ACG made the following statement on genetic testing for hereditary hemochromatosis (HH): We recommend that family members, particularly first-degree relatives, of patients diagnosed with HH should be screened for HH (strong recommendation, moderate quality of evidence). Selective screening of first-degree relatives of patients affected with type1 HH is suggested. Studies of patients with HH and their families have demonstrated that most homozygous relatives of probands demonstrate biochemical and clinical expression of the disease, not only due to the presence of the genetic mutation but also shared environmental factors that may increase the penetrance of the disease. The ACG goes on to explain that there is evidence of cost-effectiveness of screening spouses of HH patients, as well as cost-effectiveness of genetic testing for children of HH patients when compared to serum screening (p. 1206). Additionally, the ACG published a suggested algorithm for diagnosis and treatment in their 2019 practice guidelines. This algorithm includes evaluating a patient’s serum transferrin iron saturation (TS) and serum ferritin (SF), and indicates HFE genotyping if TS is 45% or greater, and/or SF is elevated (p. 1212). GeneReviews-HFE Hemochromatosis GeneReviews is an expert-authored review of current literature on a genetic disease, and goes through a rigorous editing and peer review process before being published online. They point out the following regarding transferring-iron saturation (TS) levels in hereditary hemochromatosis (in the Clinical Characteristics section, Clinical Description-Heterozygotes): Although a threshold TS of 45% may be more sensitive than higher values for detecting HFE hemochromatosis, TS of 45% may also identify heterozygotes who are not at risk of developing other clinical abnormalities. 11 Genetic Testing: Gastroenterologic Disorders (non-cancerous) V2.2023 Date of Last Revision: 3/1/2023 Lactase Insufficiency - MCM6 Targeted Variant Analysis Obermayer-Pietsch et al 2004 LCT(T/C 13910) polymorphisms are associated with lactose intolerance and reduced bone density, and they predispose to bone fractures in postmenopausal women. Genetic testing for lactose intolerance may complement common indirect methods for the detection of individuals at risk for both lactose malabsorption and osteoporosis. (p. 42) Mattar et al 2012 Genetic testing has been a new tool for the diagnosis of hypolactasia/lactase persistence but may not detect all the single nucleotide polymorphisms associated with this disorder. (p. 119) Hereditary Pancreatitis Multigene Panel American College of Gastroenterology In 2013, the American College of Gastroenterology issued guidelines on management of acute pancreatitis and included the following statement: “Genetic testing may be considered in young patients (younger than 30 years old) if no cause [of acute pancreatitis] is evident, and a family history of pancreatic disease is present (conditional recommendation, low quality of evidence).” (p. 1402) In 2020, the American College of Gastroenterology Clinical Guideline: Chronic pancreatitis (CP) recommended genetic testing in patients with clinical evidence of a pancreatitis-associated disorder or possible CP in which the etiology is unclear, especially in younger patients. At minimum, patients with idio-pathic CP should be evaluated for PRSS1, SPINK1, CFTR, and CTRC gene mutation analysis, although more extended panels with over a dozen susceptibility and modifier genes, hyper- triglyceridemia genes, and pharmacogenetics are available. (p. 325 and 330) American Pancreatic Association In 2014, the American Pancreatic Association published Practice Guidelines in Chronic Pancreatitis: Evidence-Based Report on Diagnostic Guidelines. A classification guideline for the etiology of chronic pancreatitis (CP) includes genetic mutations in PRSS1, CFTR, SPINK1, and others. (p. 7) Inflammatory Bowel Disease / Crohn’s Disease Diagnostic Algorithmic Tests 12 Genetic Testing: Gastroenterologic Disorders (non-cancerous) V2.2023 Date of Last Revision: 3/1/2023 Concert Genetics - Evidence Review for Coverage Determination - Inflammatory Bowel Disease/Crohn’s Diagnostic Algorithmic Tests There are several professional society guidelines that address appropriate diagnostic tools for IBD. These include the 2018 statement by the American College of Gastroenterology (ACG) on management of adult Crohn’s Disease, the 2019 guideline on Ulcerative Colitis in Adults by ACG, and the 2017 guideline by the European Crohn’s and Colitis Organization (ECCO) on Diagnosis and Management of Ulcerative Colitis. The ACG Crohn’s Disease and Ulcerative Colitis guidelines indicated that routine serologic testing for either disease is not recommended, with the 2019 guideline stating “we recommend against serologic antibody testing to establish or rule out a diagnosis of UC (strong recommendation, very low quality of evidence).” (p. 486 [2018 guideline], p. 385 [2019 guideline]) The ECCO evidence review and consensus concluded that the serological biomarker use of pANCAs and ASCAs for diagnosis and therapeutic decisions in ulcerative colitis is not clinically justified. (p. 653) This body of literature includes few peer reviewed published studies on the clinical validity and clinical utility of Prometheus IBD sgi Diagnostic. The peer-reviewed 2013 validation study by Plevy et al used a 17 marker Prometheus panel and determined that this panel increased the discrimination between IBD and non-IBD, as well as Crohn’s disease and ulcerative colitis compared to using serological markers alone. The current Prometheus offering, according to the laboratory website, has an additional serologic marker, to make 18 components. However, the website lists only seven serologic markers on the current panel. Given the different number of components, it is unclear if the validation study of 2013 is applicable to the currently offered test. The Plevy validation study is not prospective, nor does it document the patient outcomes when Prometheus IBD sgi Diagnostic is used to base diagnostic decisions. This is appropriate for a validation study, however additional peer-reviewed studies showing prospective clinical utility outcomes have not been published. While studies on individual biomarkers are suggestive, the panel in question includes multiple markers with a proprietary algorithm, so evidence of the clinical usefulness must be from this same panel and algorithm. Further, Shirts et al. demonstrate that the predictive value of the Prometheus IBD sgi Diagnostic test primarily comes from the three widely available markers, pANCA+, ASCA-IgA+, and IG+. At the present time, IBD Crohn’s Diagnostic Algorithmic tests such as Prometheus IBD sgi Diagnostic have INSUFFICIENT EVIDENCE in peer-reviewed publications to effectively result in improved health outcomes compared to the current standard of care. Inflammatory Bowel Disease/Crohn’s Disease Prognostic Algorithmic Tests 13 Genetic Testing: Gastroenterologic Disorders (non-cancerous) V2.2023 Date of Last Revision: 3/1/2023 Concert Genetics Evidence Review for Coverage Determination -Inflammatory Bowel Disease/Crohn’s Disease Prognostic Algorithmic Tests The results of the 2021 ECCO Scientific Workshop indicate that the PredictSURE IBD test is the only one that has sufficient evidence of clinical validity. Additionally, they point out that PredictSURE IBD currently has a clinical trial underway which may provide needed clinical utility evidence in the future. This group also has an ongoing clinical trial to further validate the biomarkers. The 2018 statement by the American College of Gastroenterology (ACG) on management of adult Crohn’s Disease states that certain genetic markers are associated with different phenotypic expressions in Crohn’s disease but testing remains a research tool at this time.” (p. 486) No other serological markers or prognostic algorithmic tests are mentioned in these guidelines. Inflammatory bowel diseases are on a heterogenous spectrum that includes both ulcerative colitis and Crohn’s disease. Two systematic reviews for serology biomarkers have been published recently, and indicate there is some promise in using these markers to distinguish ulcerative colitis from Crohn’s disease, but studies show a marked heterogeneity in serological responses among populations. Another use of serological biomarkers is to predict future complications for individual patients, but these studies are similarly hampered by varied responses. It does appear that overall, multiple markers are more useful than single markers, but more well-designed studies are needed to support which markers are the most useful. At the present time, Crohn’s Prognostic Algorithmic tests, such as PredictSURE IBD, have INSUFFICIENT evidence in peer-reviewed publications to effectively result in improved health outcomes compared to the current standard of care. At this time, the current evidence does not support health plan coverage due to a lack of evidence that prognostic serological IBD testing results in better outcomes than the current treatments. Hereditary Inflammatory Bowel Disease / Crohn’s Disease Panel Tests UpToDate (Higuchi LM and Bousvaros A, 2021) Clinical features that raise suspicion for monogenic IBD include: ● Young age of onset (eg, younger than six years, particularly younger than age two years) ● Family history of IBD and/or immunodeficiency in multiple family members, particularly with male predominance, or consanguinity Recurrent infections or unexplained fever ● 14 Genetic Testing: Gastroenterologic Disorders (non-cancerous) V2.2023 Date of Last Revision: 3/1/2023 ● Associated features of autoimmunity (eg, arthritis, primary sclerosing cholangitis, anemia, or endocrine dysfunction) ● Very severe IBD and/or resistance to conventional therapies for IBD ● Symptoms or signs suggesting hemophagocytic lymphohistiocytosis (hepatomegaly, fever, cytopenias, high ferritin) ● Lesions of the skin, nails, or hair ● Current or past history of cancer in the patient Infants or young children presenting with these features warrant careful evaluation for monogenic IBD and consultation with an immunologist. (p. 7 to 8) UpToDate (Snapper SB and McGovern DPB, 2021) “Very early onset IBD — There is a diverse spectrum of rare genetic disorders that produce IBD- like intestinal inflammation caused by genetic variants that have a large effect on gene function and typically present in infancy. Over 60 unique monogenic IBD disorders have been described that affect mucosal homeostasis in diverse ways, including: ● Epithelial barrier and response defects (eg, IKBKG, TTC7, ADAM17) ● Dysfunction of neutrophil granulocytes (eg, NCF2, NCF4, SLC37A4) ● Hyper- and autoinflammatory disorders (eg, XIAP) ● Complex defects in T- and B-cell function (eg, LRBA, CD40LG; WAS) ● Regulatory T cells and IL-10 signaling (eg, IL10R, IL10, FOXP3) Some of these disorders with gene defects that affect predominantly hematopoietic cells (eg, IL- 10R, IL-10, XIAP, FOXP3) respond to stem cell transplantation.” (p. 3 to 4) European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) (p. 24) Below is a summary of clinical features that should prompt considering a monogenic inflammatory bowel disease workup (Red flag signs): ● Age of inflammatory bowel disease (IBD) presentation ○ IBD symptom onset before age 2 years ● IBD onset before age 6 years, in particular when other red flag signs are present ○ Family history Affected family member with a suspected monogenic disorder Consanguinity Multiple family members with early-onset IBD ● Comorbidity and extraintestinal manifestations are particularly relevant for monogenic IBD diagnostic considerations when rare or atypical for patient age irrespective of organ manifestation. ○ Recurrent severe infections or atypical infections consistent with diagnostic criteria of a primary immunodeficiency Hemophagocytic lymphohistiocytosis 15 Genetic Testing: Gastroenterologic Disorders (non-cancerous) V2.2023 Date of Last Revision: 3/1/2023 Autoimmune features in particular features of Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome ○ Malignancies ○ Multiple intestinal atresias British Society of Gastroenterology This source suggests that genetic testing for monogenic disorders should be considered in adolescents and young adults who have had early onset (before 5 years of age) or particularly aggressive, refractory or unusual IBD presentations. (p. 75) Reviews, Revisions, and Approvals Policy developed REFERENCES back to top Revision Date 03/23 Approval Date 03/23 1. Kowdley KV, Brown KE, Ahn J, Sundaram V. ACG Clinical Guideline: Hereditary Hemochromatosis [published correction appears in Am J Gastroenterol. 2019 Dec;114(12):1927]. Am J Gastroenterol. 2019;114(8):1202-1218. doi:10.14309/ajg.0000000000000315 2. Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association Practice Guidelines in Chronic Pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162. doi:10.1097/MPA.0000000000000237 3. Tenner S, Baillie J, DeWitt J, Vege SS; American College of Gastroenterology. American College of Gastroenterology guideline: management of acute pancreatitis [published correction appears in Am J Gastroenterol. 2014 Feb;109(2):302]. Am J Gastroenterol. 2013;108(9):1400-1416. doi:10.1038/ajg.2013.218 4. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA; American College of Gastroenterology. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108(5):656-677. doi:10.1038/ajg.2013.79 5. AGA Institute. AGA Institute Medical Position Statement on the Diagnosis and Management of Celiac Disease. Gastroenterology. 2006;131(6):1977-1980. doi:10.1053/j.gastro.2006.10.003 6. US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, et al. Screening for Celiac Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2017;317(12):1252-1257. doi:10.1001/jama.2017.1462 16 Genetic Testing: Gastroenterologic Disorders (non-cancerous) V2.2023 Date of Last Revision: 3/1/2023 7. Barton JC, Edwards CQ. HFE Hemochromatosis. 2000 Apr 3 [Updated 2018 Dec 6]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1440/ 8. Concert Genetics. Evidence Review for Coverage Determination. Inflammatory Bowel Disease/Crohn’s Diagnostic Algorithmic Tests. 2022 9. Concert Genetics. Evidence Review for Coverage Determination. Inflammatory Bowel Disease/Crohn’s Prognostic Algorithmic Tests. 2022 10. Higuchi LM and Bousvaros A. Clinical presentation and diagnosis of inflammatory bowel disease in children. In Heyman MB, ed. UpToDate. UpToDate, 2021. Accessed November 29, 2021. https://www.uptodate.com/contents/clinical-presentation-and- diagnosis-of-inflammatory-bowel-disease-in-children 11. Uhlig HH, Charbit-Henrion F, Kotlarz D, et al. Clinical Genomics for the Diagnosis of Monogenic Forms of Inflammatory Bowel Disease: A Position Paper From the Paediatric IBD Porto Group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2021;72(3):456-473. doi:10.1097/MPG.0000000000003017 12. Turner D, Ruemmele FM, Orlanski-Meyer E, et al. Management of Paediatric Ulcerative Colitis, Part 1: Ambulatory Care-An Evidence-based Guideline From European Crohn's and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition [published correction appears in J Pediatr Gastroenterol Nutr. 2020 Dec;71(6):794]. J Pediatr Gastroenterol Nutr. 2018;67(2):257-291. doi:10.1097/MPG.0000000000002035 13. MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US). Available from: https://medlineplus.gov/genetics 14. Obermayer-Pietsch BM, Bonelli CM, Walter DE, et al. Genetic predisposition for adult lactose intolerance and relation to diet, bone density, and bone fractures. J Bone Miner Res. 2004;19(1):42-47. doi:10.1359/JBMR.0301207 15. Mattar R, de Campos Mazo DF, Carrilho FJ. Lactose intolerance: diagnosis, genetic, and clinical factors. Clin Exp Gastroenterol. 2012;5:113-121. doi:10.2147/CEG.S32368 16. Genetic Support Foundation. Genetics 101 Inheritance Patterns: Familial Pathogenic Variant. Accessed 10/4/2022. https://geneticsupportfoundation.org/genetics-101/# back to top Important Reminder This clinical policy has been developed by appropriately experienced and licensed health care professionals based on a review and consideration of currently available generally accepted standards of medical practice; peer-reviewed medical literature; government agency/program approval status; evidence-based guidelines and positions of leading national health professional 17 Genetic Testing: Gastroenterologic Disorders (non-cancerous) V2.2023 Date of Last Revision: 3/1/2023 organizations; views of physicians practicing in relevant clinical areas affected by this clinical policy; and other available clinical information. The Health Plan makes no representations and accepts no liability with respect to the content of any external information used or relied upon in developing this clinical policy. This clinical policy is consistent with standards of medical practice current at the time that this clinical policy was approved. “Health Plan” means a health plan that has adopted this clinical policy and that is operated or administered, in whole or in part, by Centene Management Company, LLC, or any of such health plan’s affiliates, as applicable. The purpose of this clinical policy is to provide a guide to medical necessity, which is a component of the guidelines used to assist in making coverage decisions and administering benefits. It does not constitute a contract or guarantee regarding payment or results. Coverage decisions and the administration of benefits are subject to all terms, conditions, exclusions and limitations of the coverage documents (e.g., evidence of coverage, certificate of coverage, policy, contract of insurance, etc.), as well as to state and federal requirements and applicable Health Plan-level administrative policies and procedures. This clinical policy is effective as of the date determined by the Health Plan. The date of posting may not be the effective date of this clinical policy. This clinical policy may be subject to applicable legal and regulatory requirements relating to provider notification. If there is a discrepancy between the effective date of this clinical policy and any applicable legal or regulatory requirement, the requirements of law and regulation shall govern. The Health Plan retains the right to change, amend or withdraw this clinical policy, and additional clinical policies may be developed and adopted as needed, at any time. This clinical policy does not constitute medical advice, medical treatment or medical care. It is not intended to dictate to providers how to practice medicine. Providers are expected to exercise professional medical judgment in providing the most appropriate care, and are solely responsible for the medical advice and treatment of members/enrollees. This clinical policy is not intended to recommend treatment for members/enrollees. Members/enrollees should consult with their treating physician in connection with diagnosis and treatment decisions. Providers referred to in this clinical policy are independent contractors who exercise independent judgment and over whom the Health Plan has no control or right of control. Providers are not agents or employees of the Health Plan. This clinical policy is the property of the Health Plan. Unauthorized copying, use, and distribution of this clinical policy or any information contained herein are strictly prohibited. Providers, members/enrollees and their representatives are bound to the terms and conditions expressed herein through the terms of their contracts. Where no such contract exists, providers, members/enrollees and their representatives agree to be bound by such terms and conditions by providing services to members/enrollees and/or submitting claims for payment for such services. 18 Genetic Testing: Gastroenterologic Disorders (non-cancerous) V2.2023 Date of Last Revision: 3/1/2023 Note: For Medicaid members/enrollees, when state Medicaid coverage provisions conflict with the coverage provisions in this clinical policy, state Medicaid coverage provisions take precedence. Please refer to the state Medicaid manual for any coverage provisions pertaining to this clinical policy. Note: For Medicare members/enrollees, to ensure consistency with the Medicare National Coverage Determinations (NCD) and Local Coverage Determinations (LCD), all applicable NCDs, LCDs, and Medicare Coverage Articles should be reviewed prior to applying the criteria set forth in this clinical policy. Refer to the CMS website at http://www.cms.gov for additional information. ©2023 Centene Corporation. All rights reserved. All materials are exclusively owned by Centene Corporation and are protected by United States copyright law and international copyright law. No part of this publication may be reproduced, copied, modified, distributed, displayed, stored in a retrieval system, transmitted in any form or by any means, or otherwise published without the prior written permission of Centene Corporation. You may not alter or remove any trademark, copyright or other notice contained herein. Centene® and Centene Corporation® are registered trademarks exclusively owned by Centene Corporation. 19