Sunflower Health Plan Concert Genetic Testing: Skeletal Dysplasia Rare Bone Disorders (PDF) Form

Concert Genetic Testing: Skeletal Dysplasia and Rare Bone Disorders V2.2023 Date of Last Revision: 3/1/2023 CONCERT GENETIC TESTING: SKELETAL DYSPLASIA AND RARE BONE DISORDERS See Important Reminder at the end of this policy for important regulatory and legal information. OVERVIEW Skeletal dysplasias are a category of rare genetic disorders that affect bones and joints and are estimated to affect 2.4 per 10,000 births, and some forms of skeletal dysplasia can be suspected based on prenatal ultrasound. There are more than 350 distinct skeletal disorders that have been described, and some skeletal dysplasias can be lethal, often due to a significantly small rib cage that restricts lung development. The osteogenesis imperfecta group of disorders are sometimes classified as skeletal dysplasias, while other times they are considered bone fragility disorders. Genetic testing has allowed for gene identification in more than two thirds of the skeletal dysplasias. Testing allows for more precise diagnosis facilitating health care providers’ care based on the established natural history of the individual disorder. For some skeletal dysplasias, knowing the specific disease causing variant or variants can impart prognostic information. A few skeletal dysplasias are currently amenable to pharmacologic therapy, though such therapies may be reserved for patients with confirmed genetic diagnosis. The familial recurrence risk and long term natural history differs based on the underlying genetic basis of disease. 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. Coding Implications 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 1 Concert Genetic Testing: Skeletal Dysplasia and Rare Bone Disorders V2.2023 Date of Last Revision: 3/1/2023 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 Coverage Criteria Sections Criteria Sections Osteogenesis Osteogenesis Imperfecta Imperfecta Example Tests (Labs) Example Tests (Labs) Osteogenesis imperfecta COL1A1 & Osteogenesis imperfecta COL1A1 & COL1A2 NGS Panel (CTGT Genetic COL1A2 NGS Panel (CTGT Genetic Testing) Testing) Common CPT Common CPT Codes Codes Common ICD Common ICD Codes Codes Ref Ref 81406, 81408, 81406, 81408, 81479 81479 Q78.0, Z82.79 3 Q78.0, Z82.79 3 Osteogenesis Imperfecta Panel Osteogenesis Imperfecta Panel (PreventionGenetics) (PreventionGenetics) Osteogenesis Imperfecta NGS Panel - Osteogenesis Imperfecta NGS Panel - Dominant & Recessive NGS (CTGT Dominant & Recessive NGS (CTGT Genetic Testing) Genetic Testing) Skeletal Disorders Panel (Invitae) Skeletal Disorders Panel (Invitae) Skeletal Dysplasia Core & Extended NGS Skeletal Dysplasia Core & Extended NGS Panel (CTGT Genetic Testing) Panel (CTGT Genetic Testing) Multigene Panel Multigene Panel Analysis for Analysis for Skeletal Dysplasia Skeletal Dysplasia or Rare Bone or Rare Bone Disorder Disorder M85, Q77, Q78 1, 7, 8 M85, Q77, Q78 1, 7, 8 81400, 81401, 81400, 81401, 81402, 81403, 81402, 81403, 81404, 81405, 81404, 81405, 81406, 81407, 81406, 81407, 81408, 81479 81408, 81479 Comprehensive Skeletal Dysplasias and Comprehensive Skeletal Dysplasias and Disorders Panel (Blueprint Genetics) Disorders Panel (Blueprint Genetics) Other Covered Skeletal Dysplasias and Rare Bone Disorders Other Covered Skeletal Dysplasias and Rare Bone Disorders varies varies Other Covered Other Covered Skeletal Skeletal Dysplasias and Dysplasias and Rare Bone Rare Bone Disorders Disorders 81400 through 81400 through 81408, 81479 81408, 81479 M85, Q77, Q78 2, 4, 5, M85, Q77, Q78 2, 4, 5, 6 6 2 Concert Genetic Testing: Skeletal Dysplasia and Rare Bone Disorders V2.2023 Date of Last Revision: 3/1/2023 OTHER RELATED POLICIES This policy document provides coverage criteria for Genetic Testing for Skeletal Dysplasia and Rare Bone Disorders. Please refer to: ● ● ● Genetic Testing: Aortopathies and Connective Tissue Disorders for coverage criteria related to Ehlers-Danlos syndrome and other connective tissue disorders. Genetic Testing: Multisystem Inherited Disorders, Intellectual Disability, and Developmental Delay for coverage criteria related to diagnostic testing for disorders that affect multiple systems. Genetic Testing: General Approach to Genetic Testing for coverage criteria related to skeletal dysplasias and rare bone 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: OSTEOGENESIS IMPERFECTA I. COL1A1 and COL1A2 variant analysis (81408, 81479) or multigene panel analysis (81406, 81408, 81479) that includes COL1A1 and COL1A2 to establish or confirm a diagnosis of osteogenesis imperfecta (OI) is considered medically necessary when: A. The member/enrollee has any of the following: 1. Fractures with minimal or no trauma in the absence of other factors, such as non-accidental trauma (NAT) or other known disorders of bone, OR 2. Short stature, often with bone deformity, OR 3. Blue/gray scleral hue, OR 4. Dentinogenesis imperfecta (DI), OR 5. Progressive, postpubertal hearing loss, OR 3 Concert Genetic Testing: Skeletal Dysplasia and Rare Bone Disorders V2.2023 Date of Last Revision: 3/1/2023 6. Ligamentous laxity or other signs of connective tissue abnormality, OR 7. Family history of OI, typically with autosomal dominant inheritance, OR 8. Fractures of varying ages and stages of healing (often of the long bones), OR 9. “Codfish” vertebrae, OR 10. Wormian bones, OR 11. Protrusio acetabuli, OR 12. Low bone mass or osteoporosis. II. COL1A1 and COL1A2 variant analysis (81408, 81479) or multigene panel analysis (81406, 81408, 81479) for osteogenesis imperfecta is considered investigational for all other indications. back to top MULTIGENE PANEL ANALYSIS FOR SKELETAL DYSPLASIA OR RARE BONE DISORDER I. Multigene panel analysis (81400, 81401, 81402, 81403, 81404, 81405, 81406, 81407, 81408, 81479) to confirm or establish a diagnosis of a skeletal dysplasia or a rare bone disorder may be considered medically necessary when: A. The member/enrollee displays one or more of the following clinical features of a skeletal dysplasia: 1. Prenatal ultrasound showing shortening of the bones of the arms and legs more than 3 standard deviations below the mean, OR 2. Prenatal ultrasound showing head circumference greater than 75th percentile, OR 3. Prenatal ultrasound showing bone irregularities (e.g., bowed, fractured, thickened, thin, undermineralized, etc.), OR 4. Prenatal ultrasound showing abnormal ribs or a small chest circumference, OR 4 Concert Genetic Testing: Skeletal Dysplasia and Rare Bone Disorders V2.2023 Date of Last Revision: 3/1/2023 5. Postnatal short stature with height or length less than 3rd percentile, AND B. The differential diagnosis includes more than one type of skeletal dysplasia or bone disorder. II. Multigene panel analysis (81400, 81401, 81402, 81403, 81404, 81405, 81406, 81407, 81408, 81479) to confirm or establish a diagnosis of a skeletal dysplasia or a rare bone disorder is considered investigational for all other indications. back to top OTHER COVERED SKELETAL DYSPLASIA AND RARE BONE DISORDERS The following is a list of conditions that have a known genetic association. Due to their relative rareness, it may be appropriate to cover these genetic tests to establish or confirm a diagnosis. I. Genetic testing to establish or confirm one of the following skeletal dysplasias or rare bone disorders to guide management is considered medically necessary when the member/enrollee demonstrates clinical features* consistent with the disorder (the list is not meant to be comprehensive, see II below): A. Achondroplasia Group 1. Achondroplasia 2. Hypochondroplasia 3. Thanatophoric Dysplasia B. Type II Collagenopathies 1. Hypochondrogenesis 2. Spondyloepiphyseal Dysplasia C. Type XI Collagen Disorders 1. Fibrochondrogenesis 2. Otospondylomegaepiphyseal Dysplasia (OSMED) D. Sulfation Disorders 1. Achondrogenesis IB 2. Atelosteogenesis II 3. Diastrophic Dysplasia 4. Chondrodysplasia with Congenital Joint Dislocations E. Filamin Disorders and Similar Disorders 1. Atelosteogenesis Type I 2. Atelosteogenesis Type III 5 Concert Genetic Testing: Skeletal Dysplasia and Rare Bone Disorders V2.2023 Date of Last Revision: 3/1/2023 3. Larsen Syndrome 4. Spondylo-Carpal-Tarsal Dysplasia F. Short-Rib Dysplasias (with and without Polydactyly) 1. Chondroectodermal Dysplasia (Ellis-van Creveld (EVC)) 2. Short-Rib Polydactyly Syndrome I, II, III, IV including Asphyxiating Thoracic Dystrophy G. Metaphyseal Dysplasias 1. Cartilage-Hair Hypoplasia H. Spondylo-Epi-(Meta)-Physeal Dysplasia 1. SEMD, Short Limb Abnormal Calcification Type I. Acromesomelic Disorders 1. Acromesomelic Dysplasia, Type Maroteaux J. Mesomelic and Rhizo-Mesomelic Dysplasias 1. Langer Type (Homozygous Dyschondrosteosis) K. Bent Bone Dysplasias 1. Campomelic Dysplasia 2. Stuve-Wiedemann Dysplasia 3. Bent Bone Dysplasia FGFR2 Type L. Slender Bone Dysplasia 1. Microcephalic Osteodysplastic Primordial Dwarfism 2. Osteocraniostenosis M. Neonatal Osteosclerotic Dysplasias 1. Bloomstrand Dysplasia 2. Caffey Disease (Infantile) 3. Raine Dysplasia N. Increased Bone Density Group 1. Osteopetrosis O. Abnormal Mineralization Group 1. Hypophosphatasia (also in Metabolic Policy) P. Multiple Epiphyseal Dysplasia and Pseudoachondroplasia Group 1. Multiple Epiphyseal Dysplasia (MED) - Autosomal Dominant 2. Multiple Epiphyseal Dysplasia (MED) - Autosomal Recessive 3. Stickler Syndrome Q. Hereditary Multiple Osteochondromas II. Genetic testing to establish or confirm the diagnosis of all other skeletal dysplasias or rare bone disorders not specifically discussed within this or another medical policy will be evaluated by the criteria outlined in General Approach to Genetic Testing (see policy for coverage criteria). 6 Concert Genetic Testing: Skeletal Dysplasia and Rare Bone Disorders V2.2023 Date of Last Revision: 3/1/2023 *Clinical features for a specific disorder may be outlined in resources such as GeneReviews, OMIM, National Library of Medicine, Genetics Home Reference, or other scholarly source. back to top NOTES AND DEFINITIONS 1. Close relatives include first, second, and third degree blood relatives: 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. Non-accidental Trauma (NAT) refers to injury that is purposely inflicted upon a child (e.g. child abuse). NAT often occurs as injury to the skin and soft, but approximately a third of NATs are fractures. back to top CLINICAL CONSIDERATIONS Osteogenesis Imperfecta versus Non-accidental trauma (NAT) 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. 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. The discussion of non- accidental trauma is as follows: OI should be distinguished from child physical abuse/non-accidental trauma (NAT). The prevalence of physical abuse is much greater than the prevalence of OI, and on rare occasions, the two can be present concurrently. Patient history, family history, physical examination, radiographic imaging, fracture investigation, and the clinical course all contribute to distinguishing OI from NAT. The overlap in clinical features includes multiple or recurrent fractures, fractures that do not match the history of trauma, and the finding of fractures of 7 Concert Genetic Testing: Skeletal Dysplasia and Rare Bone Disorders V2.2023 Date of Last Revision: 3/1/2023 varying ages and at different stages of healing. Rib fractures are much more common in NAT than in osteogenesis imperfecta. back to top BACKGROUND AND RATIONALE Osteogenesis Imperfecta GeneReviews: COL1A1/2 Osteogenesis Imperfecta 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. The recommended diagnostic testing for osteogenesis imperfecta is as follows: COL1A1/2 osteogenesis imperfecta (OI) should be suspected in individuals with the following clinical, radiographic, and laboratory features. ● ● ● ● ● ● ● Fractures with minimal or no trauma in the absence of other factors, such as non- accidental trauma (NAT) or other known disorders of bone Short stature or stature shorter than predicted based on stature of unaffected family members, often with bone deformity Blue/gray scleral hue Dentinogenesis imperfecta (DI) Progressive, postpubertal hearing loss Ligamentous laxity and other signs of connective tissue abnormality Family history of OI, usually consistent with autosomal dominant inheritance Radiographic features of OI change with age. The major findings include the following: ● ● ● ● Fractures of varying ages and stages of healing, often of the long bones but may also rarely involve ribs and skull. Metaphyseal fractures can be seen in a very small number of children with OI. Rib fractures are much more common in NAT than in OI. "Codfish" vertebrae, which are the consequence of spinal compression fractures, seen more commonly in adults. Wormian bones, defined as "sutural bones which are 6 mm by 4 mm (in diameter) or larger, in excess of ten in number, with a tendency to arrange in a mosaic pattern." Wormian bones are suggestive of but not pathognomonic for OI. Protrusio acetabuli, in which the socket of the hip joint is too deep and the acetabulum bulges into the cavity of the pelvis causing intrapelvic protrusion of the acetabulum. 8 Concert Genetic Testing: Skeletal Dysplasia and Rare Bone Disorders V2.2023 Date of Last Revision: 3/1/2023 ● Low bone mass or osteoporosis detected by dual energy x-ray absorptiometry (DEXA). Bone density can be normal, especially in individuals with OI type I, as DEXA measures mineral content rather than collagen. Laboratory features ● Serum concentrations of vitamin D, calcium, phosphorous, and alkaline phosphatase are typically normal; however, alkaline phosphatase may be elevated acutely in response to fracture and rare instances of abnormally low alkaline phosphatase levels have been noted anecdotally in severe OI. Analysis of type 1 collagen synthesized in vitro by culturing dermal fibroblasts obtained from a small skin biopsy reflects the structure and quantity of the collagen. The sensitivity of biochemical testing is approximately 90% in individuals with clinically confirmed OI. Biochemical analysis is essentially no longer used clinically with the advances in molecular diagnostics. ● “A multigene panel that includes COL1A1, COL1A2, and other genes of interest is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and variants in genes that do not explain the underlying phenotype.” Multigene Panel Analysis for Skeletal Dysplasia or Rare Bone Disorder Krakow et al 2009 A guideline for prenatal diagnosis of fetal skeletal dysplasias (Krakow, Lachman, Rimoin, 2009) recommends the follow criteria: ● Fetuses with long bone measurements at or less than the 5th centile or >3 SD below the mean should be evaluated in a center with expertise in the recognition of skeletal dysplasias. If the patient cannot travel, arrangements may be able to be made for evaluation of ultrasound videotapes or hard copy images. The following fetal ultrasound measurements should be visualized and plotted against normative values: fetal cranium (biparietal diameter and head circumference), facial profile, mandible, clavicle, scapula, chest circumference, vertebral bodies, all fetal long bones, and the hands and feet. Fetuses with long bone parameters >3 SD below the mean should be strongly suspected of having a skeletal dysplasia, especially if the head circumference is greater than the 75th centile Lethality should be determined by chest circumference to abdominal circumference ratio and/or femur length to abdominal circumference measurement ratio. A chest-to abdominal circumference ratio of <0.6 or femur length to abdominal circumference ratio ● ● 9 Concert Genetic Testing: Skeletal Dysplasia and Rare Bone Disorders V2.2023 Date of Last Revision: 3/1/2023 of 0.16 strongly suggests a perinatal lethal disorder, although there are exceptions. The findings should be conveyed to the physicians caring for the patient and to the patient. (p. 5) In addition, close attention should be paid to the shape and mineralization pattern of the fetal calvarium and fetal skeleton (poor or ectopic mineralization). Determining the elements of the skeleton that are abnormal, coupled with the findings of mineralization and shape of the bones can aid in diagnosis. (p. 3) American College of Medical Genetics and Genomics (ACMG) For diagnosis of genetic causes of short stature, the American College of Medical Genetics practice guideline for evaluation of short stature (Seaver et al, 2009) is as follows: The definition most commonly used for short stature is height-for-age less than two standard deviations below average for gender, which is demonstrated on the standard growth curves as a length or height less than the 3rd centile. (p. 466) Nikkel 2017 Nikkel (2017) indicated the value of multigene panels for skeletal dysplasias with the following: ● The use of multigene panels, using next generation sequence technology, has improved our ability to quickly identify the genetic etiology, which can impact management. (p. 419) One should ensure that a panel contains all the genes under consideration and there is appropriate deletion/duplication analysis when such pathogenic changes are noted to occur in the gene. (p. 420 to 421) ● Other Covered Skeletal Dysplasia and Rare Bone Disorders International Skeletal Dysplasia Society The International Skeletal Dysplasia Society published an updated categorization of skeletal dysplasias (Mortier, 2019). This newest and tenth version of the Nosology comprises 461 different diseases that are classified into 42 groups based on their clinical, radiographic, and/or molecular phenotypes. Remarkably, pathogenic variants affecting 437 different genes have been found in 425/461 (92%) of these disorders. By providing a reference list of recognized entities and their causal genes, the Nosology should help clinicians achieve accurate 10 Concert Genetic Testing: Skeletal Dysplasia and Rare Bone Disorders V2.2023 Date of Last Revision: 3/1/2023 diagnoses for their patients and help scientists advance research in skeletal biology. (p. 2393) Reviews, Revisions, and Approvals Policy developed REFERENCES back to top Revision Date 03/23 Approval Date 03/23 1. Seaver LH, Irons M; American College of Medical Genetics (ACMG) Professional Practice and Guidelines Committee. ACMG practice guideline: genetic evaluation of short stature [published correction appears in Genet Med. 2009 Oct;11(10):765]. Genet Med. 2009;11(6):465-470. doi:10.1097/GIM.0b013e3181a7e8f8 2. Mortier GR, Cohn DH, Cormier-Daire V, et al. Nosology and classification of genetic skeletal disorders: 2019 revision. Am J Med Genet A. 2019;179(12):2393-2419. doi:10.1002/ajmg.a.61366 3. Steiner RD, Basel D. COL1A1/2 Osteogenesis Imperfecta. 2005 Jan 28 [Updated 2021 May 6]. In: Adam MP, Mirzaa GMArdinger 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/NBK1295/ 4. 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/NBK1116/ 5. Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD). World Wide Web URL: https://omim.org/ 6. MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US). Available from: https://medlineplus.gov/genetics/ 7. Nikkel SM. Skeletal Dysplasias: What Every Bone Health Clinician Needs to Know. Curr Osteoporos Rep. 2017;15(5):419-424. doi:10.1007/s11914-017-0392-x 8. Krakow D, Lachman RS, Rimoin DL. Guidelines for the prenatal diagnosis of fetal skeletal dysplasias. Genet Med. 2009;11(2):127-133. doi:10.1097/GIM.0b013e3181971ccb Important Reminder back to top 11 Concert Genetic Testing: Skeletal Dysplasia and Rare Bone Disorders V2.2023 Date of Last Revision: 3/1/2023 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 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 12 Concert Genetic Testing: Skeletal Dysplasia and Rare Bone Disorders V2.2023 Date of Last Revision: 3/1/2023 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. 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. 13