Protocol Genetic Testing for Nonsyndromic Hearing Loss (20487) Medical Benefit Effective Date: 04/01/14 Next Review Date: 01/15 Preauthorization Yes Review Dates: 01/14 The following Protocol contains medical necessity criteria that apply for this service. It is applicable to Medicare Advantage products unless separate Medicare Advantage criteria are indicated. If the criteria are not met, reimbursement will be denied and the patient cannot be billed. Preauthorization is required. Please note that payment for covered services is subject to eligibility and the limitations noted in the patient s contract at the time the services are rendered. Description Congenital deafness and childhood-onset hearing loss is caused by genetic mutations in a large percentage of cases. Genetic testing for hearing loss is primarily intended either to determine whether hearing loss is hereditary, or to determine carrier status of parents in order to better define the likelihood of hearing loss in their offspring. Background Description of disease. Hearing loss is a common birth defect. Approximately one of every 500 newborns in developed countries is affected by bilateral, permanent hearing loss of moderate or greater severity ( 40 db). (1) Syndromic hearing loss refers to hearing loss associated with other medical or physical findings. Since syndromic hearing loss occurs as part of a syndrome of multiple clinical manifestations, it is often recognized more readily as hereditary in nature. Nonsyndromic hearing loss (NSHL) is defined as hearing loss that is not associated with other physical signs or symptoms. For NSHL, it is more difficult to determine whether the etiology is hereditary or acquired, since by definition there are no other clinical manifestations. NSHL accounts for 70% to 80% of genetically-determined deafness. (2) Autosomal recessive patterns of inheritance predominate and account for 80% of congenital NSHL. A typical clinical presentation of autosomal recessive NSHL involves the following characteristics: Sensorineural hearing loss Mild to profound (more commonly) degree of hearing impairment Congenital onset Usually non-progressive No associated medical findings The majority of the remaining 20% of patients have an autosomal dominant inheritance pattern, with a small number having X-linked or mitochondrial inheritance. Patients with autosomal dominant inheritance typically show progressive NSHL which begins in the second through fourth decades of life. (3) Diagnosis of nonsyndromic hearing loss requires an evaluation with appropriate core medical personnel with expertise in the genetics of hearing loss, dysmorphology, audiology, otolaryngology, genetic counseling, and communication with deaf patients. The evaluation should include a family history, as well as a physical examination consisting of otologic examination, airway examination, documentation of dysmorphisms and Page 1 of 6
neurologic evaluation. (4) However, the clinical diagnosis of nonsyndromic hearing loss is non-specific since there are a number of underlying etiologies, and often it cannot be determined with certainty whether a genetic cause for hearing loss exists. Treatment of congenital and early-onset hearing loss typically involves enrollment in an educational curriculum for hearing impaired persons and fitting with an appropriate hearing aid. In some patients with profound deafness, a cochlear implant can be performed. Early identification of infants with hearing impairment may be useful in facilitating early use of amplification by six months of age and early intervention to achieve ageappropriate communication, speech and language development. (5) Delays in development of hearing treatment have been shown to delay development of communication. The primary method for identification of hearing impairment has been newborn screening with audiometry. Genetic testing has not been proposed as a primary screen for hearing loss. Genetic mutations in NSHL. The genetic loci on which mutations associated with NSHL are usually found are termed DFN, and NSHL is sometimes called DFN-associated hearing loss. DFNA3-associated NSHL is caused by autosomal dominant mutations present in the GJB2 or GJB6 genes, which alters the coding sequence for the connexin proteins Cx26 or Cx30, respectively. (6) DFNB1-associated NSHL are autosomal recessive syndromes in which more than 99% of cases are caused by mutations to the GJB2 gene with less than 1% of remaining cases arising from mutations to GJB6. (7) A list of available tests for genetic mutations at the DFNA3 and DFNB1 loci is given in Table 1. There are more than 300 individual mutations known to be associated with NSHL. (8) Two of the most commonly mutated genes are GJB2 and GJB6. GJB2 is a small gene with a single coding exon. Mutations of this gene are most common in NSHL, causing an estimated 50% of the cases on NSHL. (9) The carrier rate in the general population for a recessive deafness-causing GJB2 mutation is approximately one in 33. (1) Specific mutations have been observed to be more common in certain ethnic populations. (10, 11) Mutations in the GJB2 gene will impact expression of the Cx26 connexin protein and almost always cause pre-lingual, but not necessarily congenital, deafness. (8) Differing mutations to GJB2 can present high phenotypic variation, but it has been demonstrated that it is possible to correlate the type of associated hearing loss with findings on molecular analysis. Mutations in the GJB6 gene are the second most common genetic defect in NSHL and lead to similar effects on abnormal expression of connexin protein Cx30. However, GJB6 mutations are much less common than mutations in GJB2. Of all the patients with NSHL, approximately 3% are found to have a mutation in the GJB6 gene. Table 1. Clinical Characteristics and Testing Methods for GJB2 and GJB6 Mutations at the DFNA3 and DFNB1 Loci Locus Name Gene Symbol Onset Audioprofile Test Method Mutations Detected DFNA3 GJB2 Prelingual High frequency progressive DFNA3 GJB6 Prelingual High frequency progressive Sequence Analysis/Mutation Scanning Targeted Mutation Analysis Deletion/duplication analysis Sequence Analysis/Mutation Scanning Targeted Mutation Analysis Deletion/duplication analysis Sequence Variants Specified sequence variants Exonic or whole-gene deletions/ duplications Sequence Variants Specified sequence variants Exonic or whole-gene deletions/ duplications Page 2 of 6
Locus Name Gene Symbol Onset Audioprofile Test Method Mutations Detected DFNB1 GJB2 Prelingual Usually stable Sequence analysis 2 GJB2 sequence variants Deletion/duplication analysis 4 DFNB1 GJB6 Prelingual Usually stable Targeted Mutation Analysis GJB6 deletions Exon(s) or whole-gene deletions Mutation analysis for GJB6 and GJB2 mutations can be performed by Sanger sequencing analysis of individual genes. This method has a high degree of validity and reliability, but is limited by the ability to sequence one gene at a time. With Sanger sequencing, the gene with the most common mutations is generally sequenced first, followed by sequencing of additional genes if a pathogenic mutation is not found. In addition to the most common mutations that are associated with NSHL, GJB6 and GJB2, there are many less common pathologic mutations. Some of these are: ACTG1, CDH23, CLDN14, COCH, COL11A2, DFNA5, DFNB31, DFNB59, ESPN, EYA4, GJB2, GJB6, KCNQ4, LHFPL5, MT-TS1, MYO15A, MYO6, MYO7A, OTOF, PCDH15, POU3F4, SLC26A4, STRC, TECTA, TMC1, TMIE, TMPRSS3, TRIOBP, USH1C, and WFS1 genes. Because of the large number of genes associated with NSHL, there are a variety of genetic panels for hereditary deafness. Next generation genetic sequencing technology allows targeted sequencing of multiple genes simultaneously, expanding the ability to examine multiple genes. These panels are alternatives to sequencing of individual genes such as GJB6 and GJB2. Some examples of these panels are given in Table 3. These panels include the most common genes associated with NSHL. They may also include many of the less common genes associated with NSHL, as well as genes that are associated with syndromic hearing loss. Regulatory Status No FDA-cleared molecular diagnostic tests were found. Thus, molecular evaluation is offered as a laboratorydeveloped test. Clinical laboratories may develop and validate tests in-house (laboratory-developed tests, formerly home-brew ) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). The laboratory offering the service must be licensed by CLIA for high-complexity testing. More than a dozen commercial laboratories currently offer a wide variety of diagnostic procedures for GJB2 and GJB6 genetic testing. Related Protocols Preimplantation Genetic Testing Cochlear Implant Policy (Formerly Corporate Medical Guideline) Genetic testing for NSHL mutations (GJB2, GJB6 and other NSHL-related mutations) in individuals with nonsyndromic hearing loss to confirm the diagnosis of hereditary nonsyndromic hearing loss (see Policy Guidelines) may be considered medically necessary. Preconception genetic testing (carrier testing) for nonsyndromic hearing loss (NSHL) mutations (GJB2, GJB6 and other NSHL-related mutations) in parents may be considered medically necessary when at least one of the following conditions has been met: Offspring with hereditary NSHL; OR One or both parents with suspected NSHL; OR First- or second-degree relative affected with hereditary NSHL; OR First-degree relative with offspring who is affected with hereditary NSHL Page 3 of 6
Genetic testing for nonsyndromic hearing loss mutations is considered investigational for all other situations (except as addressed in Related Protocols, e.g., Preimplantation Genetic Testing). Policy Guideline The definition of NSHL is hearing loss that is not associated with other physical signs and symptoms. It is differentiated from syndromic hearing loss, which is hearing loss associated with other signs and symptoms characteristic of a specific syndrome. Physical signs of a syndrome often include dysmorphic changes in the maxillofacial region and/or malformations of the external ears. Malfunction of internal organs may also be part of a syndrome. The physical signs can be subtle and easily missed on physical exam, therefore exclusion of syndromic findings is ideally done by an individual with expertise in identifying dysmorphic physical signs. The phenotypic presentation of NSHL varies, but generally involves the following features: Sensorineural hearing loss Mild to profound (more commonly) degree of hearing impairment Congenital onset Usually non-progressive Genetic evaluation and counseling should be offered to all patients who are being considered for NSHL genetic testing. Genetic evaluation and counseling can help define the familial patterns of inheritance, exclude the presence of syndromic hearing loss, and provide information to patients on the future risk of NSHL in offspring. In addition to mutations in the GJB6 and GJB2 genes, there are many less common pathologic mutations found in other genes. Some of these are: ACTG1, CDH23, CLDN14, COCH, COL11A2, DFNA5, DFNB31, DFNB59, ESPN, EYA4, GJB2, GJB6, KCNQ4, LHFPL5, MT-TS1, MYO15A, MYO6, MYO7A, OTOF, PCDH15, POU3F4, SLC26A4, STRC, TECTA, TMC1, TMIE, TMPRSS3, TRIOBP, USH1C, and WFS1 genes. Testing for mutations associated with NSHL should be confined to known pathologic mutations. While research studies using genome-wide associations have uncovered numerous single-nucleotide polymorphisms (SNPs) and copy number variations (CNVs) associated with NSHL, (12, 13) the clinical significance of these findings is unclear. For carrier testing, outcomes are expected to be improved if parents alter their reproductive decision-making as a result of genetic test results. This may occur through the use of preimplantation genetic testing in combination with in vitro fertilization. Other ways that prospective parents may alter their reproductive choices are to proceed with attempts at pregnancy, or to avoid attempts at pregnancy, based on carrier testing results. Services that are the subject of a clinical trial do not meet our Technology Assessment Protocol criteria and are considered investigational. For explanation of experimental and investigational, please refer to the Technology Assessment Protocol. It is expected that only appropriate and medically necessary services will be rendered. We reserve the right to conduct prepayment and postpayment reviews to assess the medical appropriateness of the above-referenced procedures. Some of this Protocol may not pertain to the patients you provide care to, as it may relate to products that are not available in your geographic area. Page 4 of 6
References We are not responsible for the continuing viability of web site addresses that may be listed in any references below. 1. Smith RJH, Shearer AE, Hildebrand MS et al. Deafness and Hereditary Hearing Loss Overview. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, eds. GeneReviews. Seattle (WA) 1993. 2. Morton CC, Nance WE. Newborn hearing screening--a silent revolution. N Engl J Med 2006; 354(20):2151-64. 3. Matsunaga T. Value of genetic testing in the otological approach for sensorineural hearing loss. Keio J Med 2009; 58(4):216-22. 4. Genetic Evaluation of Congenital Hearing Loss Expert Panel. Genetics Evaluation Guidelines for the Etiologic Diagnosis of Congenital Hearing Loss. Genetic Evaluation of Congenital Hearing Loss Expert Panel. ACMG statement. Genet Med 2002; 4(3):162-71. 5. Milunsky JM, Maher TA, Yosunkaya E et al. Connexin-26 gene analysis in hearing-impaired newborns. Genet Test 2000; 4(4):345-9. 6. Smith RJH, Sheffield AM, Van Camp G. Nonsyndromic Hearing Loss and Deafness, DFNA3. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, eds. GeneReviews. Seattle (WA) 1993. 7. Smith RJH, Van Camp G. Nonsyndromic Hearing Loss and Deafness, DFNB1. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, eds. GeneReviews. Seattle (WA) 1993. 8. Linden Phillips L, Bitner-Glindzicz M, Lench N et al. The future role of genetic screening to detect newborns at risk of childhood-onset hearing loss. Int J Audiol 2013; 52(2):124-33. 9. Apps SA, Rankin WA, Kurmis AP. Connexin 26 mutations in autosomal recessive deafness disorders: a review. Int J Audiol 2007; 46(2):75-81. 10. Green GE, Scott DA, McDonald JM et al. Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness. JAMA 1999; 281(23):2211-6. 11. Bitner-Glindzicz M. Hereditary deafness and phenotyping in humans. Br Med Bull 2002; 63:73-94. 12. Tsai EA, Berman MA, Conlin LK et al. PECONPI: A novel software for uncovering pathogenic copy number variations in non-syndromic sensorineural hearing loss and other genetically heterogeneous disorders. American journal of medical genetics. Part A 2013; 161(9):2134-47. 13. Park MH, Park HJ, Kim KJ et al. Genome-wide SNP-based linkage analysis for ADNSHL families identifies novel susceptibility loci with positive evidence for linkage. Genes & genetic systems 2011; 86(2):117-21. 14. Year 2007 position statement: Principles and guidelines for early hearing detection and intervention programs. Pediatrics 2007; 120(4):898-921. 15. Abe S, Yamaguchi T, Usami S. Application of deafness diagnostic screening panel based on deafness mutation/gene database using invader assay. Genet Test 2007; 11(3):333-40. 16. Gardner P, Oitmaa E, Messner A et al. Simultaneous multigene mutation detection in patients with sensorineural hearing loss through a novel diagnostic microarray: a new approach for newborn screening follow-up. Pediatrics 2006; 118(3):985-94. 17. Li CX, Pan Q, Guo YG et al. Construction of a multiplex allele-specific PCR-based universal array (ASPUA) and its application to hearing loss screening. Hum Mutat 2008; 29(2):306-14. 18. Siemering K, Manji SS, Hutchison WM et al. Detection of mutations in genes associated with hearing loss using a microarray-based approach. J Mol Diagn 2006; 8(4):483-9; quiz 528. Page 5 of 6
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