Concert Genetic Testing: Hearing Loss (PDF) Form

Concert Genetic Testing: Hearing Loss V2.2023 Date of Last Revision 3/1/2023 CONCERT GENETIC TESTING: HEARING LOSS See Important Reminder at the end of this policy for important regulatory and legal information. OVERVIEW Hereditary hearing loss can be classified as syndromic or nonsyndromic. Syndromic hearing loss refers to hearing loss associated with other medical or physical findings, including visible abnormalities of the external ear. Because syndromic hearing loss occurs as part of a syndrome of multiple clinical manifestations, it is often recognized more readily as hereditary. Nonsyndromic hearing loss is defined as hearing loss not associated with other physical signs or symptoms. Nonsyndromic hearing loss accounts for 70% to 80% of genetically determined deafness, and it is more difficult to determine whether the etiology is hereditary or acquired.
This policy primarily focuses on the use of genetic testing to identify a cause of suspected hereditary hearing loss. The diagnosis of syndromic hearing loss can be made on the basis of associated clinical findings. However, at the time of hearing loss presentation, associated clinical findings may not be apparent; furthermore, variants in certain genetic loci may cause both syndromic and nonsyndromic hearing loss. Given this overlap, the policy focuses on genetic testing for hereditary hearing loss more generally. 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 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 1

Concert Genetic Testing: Hearing Loss
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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 Hereditary Hearing Loss Example Tests (Labs) Common CPT Codes Common ICD Codes Ref Known Familial Variant Analysis for Hereditary Hearing Loss GJB2 and GJB6 Sequencing and/or Deletion/ Duplication Analysis or Multigene Panel Analysis GJB2 Targeted Mutation Analysis 81253 GJB6 Targeted Mutation Analysis
81403 GJB2 Sequencing Analysis 81252 GJB2 Deletion/Duplication Analysis 81479 GJB6 Common Variant Analysis 81254 GJB6 Sequencing Analysis 81479 1, 2
H90 through H90.8, H90.A through H90.A3, H91.3 through H91.93 Hearing Loss Panel (GeneDx) 81430, 81431 Comprehensive Hearing Loss NGS Panel (Sequencing & Deletion/Duplication) (Fulgent Genetics) Hearing Loss and Deafness - Comprehensive (PreventionGenetics) OTHER RELATED POLICIES This policy document provides coverage criteria for genetic testing for hereditary hearing loss. Please refer to:
● Genetic Testing: Prenatal and Preconception Carrier Screening for coverage criteria related to carrier screening for hereditary hearing loss. 2

Concert Genetic Testing: Hearing Loss
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● Genetic Testing: Multisystem Inherited Disorders, Intellectual Disability, and Developmental Delay for coverage criteria related to genetic disorders that affect multiple organ systems ● Genetic Testing: General Approach to Genetic Testing for coverage criteria related to genetic testing for hearing loss 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: HEREDITARY HEARING LOSS Known Familial Variant Analysis for Hereditary Hearing Loss I. Targeted variant analysis for known familial variant(s) to establish a diagnosis of hereditary hearing loss (81253, 81403) is considered medically necessary when: A. The member/enrollee has a close relative with pathogenic or likely pathogenic variant(s) in GJB2, GJB6, or another gene known to cause hereditary hearing loss. back to top GJB2 and GJB6 Sequencing and/or Deletion/Duplication Analysis or Multigene Panel Analysis I. GJB2 sequencing and/or deletion/duplication (81252, 81479) and/or GJB6 sequencing and/or deletion/duplication analysis (81254, 81479) or multigene panel analysis (81430, 81431) to establish a diagnosis of hereditary hearing loss is considered medically necessary when: A. The member/enrollee has hearing loss, AND B. There is no known acquired cause of the hearing loss (i.e., TORCH infections [Toxoplasma gondii, other agents, rubella, cytomegalovirus, and herpes simplex virus], bacterial infection, age-related or noise-related hearing loss). 3

Concert Genetic Testing: Hearing Loss
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II. GJB2 sequencing and/or deletion/duplication (81252, 81479) and/or GJB6 sequencing and/or deletion/duplication analysis (81254, 81479) or multigene panel analysis (81430, 81431) to establish a diagnosis of hereditary hearing loss is considered investigational for all other indications. 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 back to top CLINICAL CONSIDERATIONS If there is not a high suspicion for a specific hearing loss etiology, ideally the evaluation should occur in a stepwise fashion. About 50% of individuals with autosomal recessive hereditary hearing loss have pathogenic variants in the GJB2 gene, in the other 50% of patients with apparent autosomal recessive hereditary hearing loss, numerous other genes are implicated. There is no single identifiable gene responsible for most cases of autosomal dominant hereditary hearing loss.
   If there is suspicion for autosomal recessive congenital hearing loss, it would be reasonable to begin with testing of GJB2 and GJB6 and if testing is negative, screening for the other genes associated with hearing loss with a multigene panel would be efficient. An alternative strategy for suspected autosomal recessive or autosomal dominant hearing loss would be to obtain a multigene panel that includes GJB2 and GJB6 as a first step.
   Given the extreme heterogeneity in genetic causes of hearing loss, these 2 strategies may be considered reasonably equivalent. back to top 4

   Concert Genetic Testing: Hearing Loss
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   BACKGROUND AND RATIONALE Known Familial Variant Analysis for Hereditary Hearing Loss 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. GJB2 and GJB6 Sequencing and/or Deletion Duplication Analysis or Multigene Panel Analysis American College of Medical Genetics and Genomics (ACMG) The American College of Medical Genetics and Genomics (ACMG) published guidelines in 2022 to guide genetics evaluation for individuals with hearing loss: “For individuals lacking physical findings suggestive of a known syndrome, a tiered diagnostic approach should be implemented. Unless clinical and/or family history suggests a specific genetic etiology, comprehensive HL gene panel testing should be initiated.” (page 9) The guidelines state the following: “Although nonsyndromic HL [hearing loss] demonstrates high genetic heterogeneity, the DFNB1 locus, which includes the GJB2 gene encoding the gap junction protein connexin 26 and the GJB6 gene encoding the gap junction protein connexin 30, accounts for an estimated 50% of all autosomal recessive nonsyndromic HL and 15% to 40% of all deaf individuals in a variety of populations.” (page 3) GeneReviews: Hereditary Hearing Loss and Deafness Overview 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. In the section that discusses possible differential diagnosis for hereditary hearing loss and deafness, it states: 5

   Concert Genetic Testing: Hearing Loss
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   In developed countries approximately 80% of congenital hearing loss is due to genetic causes and the remainder to environmental (acquired) causes. Acquired causes should be differentiated from genetic causes to inform the evaluation and required ancillary testing. Acquired hearing loss in children commonly results from prenatal infections from ‘TORCH’ organisms…or postnatal infections (such as CMV). Acquired hearing loss in adults is most often attributed to environmental factors. Reviews, Revisions, and Approvals Policy developed REFERENCES back to top Revision Date 03/23 Approval Date 03/23

2. Li MM, Tayoun AA, DiStefano M, et al. Clinical evaluation and etiologic diagnosis of hearing loss: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2022;24(7):1392-1406.

3. Shearer AE, Hildebrand MS, Smith RJH. Hereditary Hearing Loss and Deafness Overview. 1999 Feb 14 [Updated 2017 Jul 27]. 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/NBK1434/

   3. 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 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. 6

   Concert Genetic Testing: Hearing Loss
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   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.
   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 7

   Concert Genetic Testing: Hearing Loss
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   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. 8