Genetic Testing for Hereditary Hearing Loss

MEDICAL POLICY – 12.04.87 Genetic Testing for Hereditary Hearing Loss BCBSA Ref. Policy: 2.04.87 Effective Date: July 1, 2017 RELATED MEDICAL POLIC...
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MEDICAL POLICY – 12.04.87

Genetic Testing for Hereditary Hearing Loss BCBSA Ref. Policy: 2.04.87 Effective Date:

July 1, 2017

RELATED MEDICAL POLICIES:

Last Revised:

June 6, 2017

12.04.305 Preimplantation Genetic Testing in Embryos

Replaces:

2.04.87

Select a hyperlink below to be directed to that section. POLICY CRITERIA | CODING | RELATED INFORMATION EVIDENCE REVIEW | REFERENCES | HISTORY

∞ Clicking this icon returns you to the hyperlinks menu above. Introduction There are several things that can cause hearing loss. It can be caused by illness, injuries, or even certain medications. A baby who is born too soon or who needs to use a breathing machine (ventilator) after birth may develop hearing loss. Complicating this even more is that hearing loss can be “syndromic.” This means that a person has other symptoms in addition to hearing loss. “Nonsyndromic” hearing loss means a person doesn’t have any other symptoms. Genetic changes are the root cause of some hearing loss. If more than one person in a family has hearing loss, it is called familial hearing loss. Even in families with genetic hearing loss, it may not be caused by changes to any of the genes known to be associated with hearing. This policy describes when genetic testing for hearing loss may be considered medically necessary.

Note:

The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered.

Policy Coverage Criteria

Genetic Testing

Medical Necessity

Variants in hereditary

Genetic testing for variants in hereditary hearing loss genes

hearing loss genes

(GJB2, GJB6, and other hereditary hearing loss-related genes) in individuals with hearing loss in order to confirm the diagnosis of hereditary hearing loss (see Related Information) may be considered medically necessary. Genetic testing for hereditary hearing loss variants is considered investigational for all other situations, including, but not limited to, testing in patients without hearing loss (except as addressed in Related Policies).

Preconception genetic

Preconception genetic testing (carrier testing) for variants in

testing for hereditary

hereditary hearing loss genes (GJB2, GJB6, and other

hearing loss variants

hereditary hearing loss-related genes) in parents may be considered medically necessary when at least one of the following conditions has been met: 

Offspring with hereditary hearing loss

OR 

One or both parents with suspected hereditary hearing loss

OR 

First- or second-degree relative affected with hereditary hearing loss

OR 

First-degree relative with offspring who is affected with hereditary hearing loss

Coding

Code

Description

CPT 81252

GJB2 (gap junction protein, beta 2, 26kDa; connexin 26) (eg, nonsyndromic hearing loss) gene analysis, full gene sequence

81253

GJB2 (gap junction protein, beta 2, 26kDa, connexin 26) (eg, nonsyndromic hearing loss) gene analysis; known familial variants

81254

GJB6 (gap junction protein, beta 6, 30kDa, connexin 30)(eg, nonsyndromic hearing loss) gene analysis, common variants (eg, 309kb [del(GJB6-D13S1830)] and 232kb

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Code

Description [del(GJB6-D13S1854)])

81430

Hearing loss (eg, nonsyndromic hearing loss, Usher syndrome, Pendred syndrome); genomic sequence analysis panel, must include sequencing of at least 60 genes, including CDH23, CLRN1, GJB2, GPR98, MTRNR1, MYO7A, MYO15A, PCDH15, OTOF, SLC26A4, TMC1, TMPRSS3, USH1C, USH1G, USH2A, and WFS1

81431

Hearing loss (eg, nonsyndromic hearing loss, Usher syndrome, Pendred syndrome); duplication/deletion analysis panel, must include copy number analyses for STRC and DFNB1 deletions in GJB2 and GJB6 genes

Note:

CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). HCPCS codes, descriptions and materials are copyrighted by Centers for Medicare Services (CMS).

Related Information

Hereditary hearing loss can be classified as syndromic or non-syndromic. The definition of nonsyndromic hearing loss (NSHL) is hearing loss that is not associated with other physical signs and symptoms at the time of hearing loss presentation. 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

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 may be able to 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

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may cause both syndromic and NSHL. Given this overlap, the policy focuses on genetic testing for hereditary hearing loss more generally. In addition to variants in the GJB6 and GJB2 genes, there are many less common pathologic variants 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. Targeted testing for variants associated with hereditary hearing loss should be confined to known pathogenic variants. While research studies using genome-wide associations have uncovered numerous single-nucleotide variants and copy number variations associated with hereditary hearing loss, 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.

Testing Strategy Evaluation of a patient with suspected hereditary hearing loss should involve a careful physical exam and family history to assess for associated clinical findings that may point to a specific syndrome or non-syndromic cause of hearing loss (eg, infectious, toxic, autoimmune, other causes). Consideration should also be given to temporal bone computed tomography scanning in cases of progressive hearing loss and to testing for cytomegalovirus (CMV) in infants with sensorineural hearing loss. If there is no high suspicion for a specific hearing loss etiology, ideally the evaluation should occur in a step-wise fashion. About 50% of individuals with autosomal recessive hereditary hearing loss have pathogenic variants in the GJB2 gene. In the remainder of patients with apparent autosomal recessive hereditary hearing loss, numerous other genes are implicated. In autosomal dominant hereditary hearing loss, there is no single identifiable gene responsible for most cases. If there is suspicion for autosomal recessive congenital hearing loss, it would be reasonable to begin with testing of GJB2 and GJB6. If this 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

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heterogeneity in genetic causes of hearing loss, these 2 strategies may be considered reasonably equivalent.

Genetic Counseling Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Evidence Review

Background

Hereditary Hearing Loss Hearing loss is a common birth defect. Approximately 1 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, 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 in nature. 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, because by definition, there are no other clinical manifestations at the time of the hearing loss presentation. NSHL accounts for 70% to 80% of genetically determined deafness.2

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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

Most 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 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 neurologic evaluation.4 However, the clinical diagnosis of nonsyndromic hearing loss is non-specific because there are a number of underlying etiologies, and often it cannot be determined with certainty whether a genetic cause for hearing loss exists.

Treatment 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 6 months of age and early intervention to achieve age-appropriate communication, speech, and language development.5 Delays in development of hearing treatment have been shown to delay development of communication. The primary method for

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identification of hearing impairment has been newborn screening with audiometry. Genetic testing has not been proposed as a primary screen for hearing loss.

Genetics of Hereditary Hearing Loss Genes associated with hereditary hearing loss may be associated with an autosomal dominant, autosomal recessive, X-linked, or mitochondrial inheritance pattern. The genetic loci on which variants associated with hereditary hearing loss are usually found are termed DFN, and hereditary hearing loss is sometimes called DFN-associated hearing loss. DFN loci are named based on their mode of inheritance: DFNA associated with autosomal dominant inheritance; DFNB with autosomal recessive inheritance; and DFNX with x-linked inheritance. Two DFN loci commonly associated with hereditary hearing loss are DFNA3 and DFNB1, both of which map to chromosome 13q12. DFNA3-associated hereditary hearing loss is caused by autosomal dominant variants present in the GJB2 or GJB6 genes.6 DFNB1-associated hereditary hearing loss are autosomal recessive syndromes in which more than 99% of cases are caused by variants to the GJB2 gene with less than 1% of remaining cases arising from variants to GJB6.7 A list of available tests for genetic variants at the DFNA3 and DFNB1 loci is given in Table 1. Two of the most commonly mutated genes are GJB2 and GJB6. GJB2 is a small gene with a single coding exon. Variants of this gene are most common in hereditary hearing loss, causing an estimated 50% of the cases of nonsyndromic hereditary hearing loss.8 The carrier rate in the general population for a recessive deafness-causing GJB2 mutation is approximately 1 in 33.1 Specific variants have been observed to be more common in certain ethnic populations.9,10 Variants in the GJB2 gene will impact expression of the Cx26 connexin protein and almost always cause prelingual, but not necessarily congenital, deafness.11 Differing variants 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. A systematic review of publications reporting GJB2 mutation prevalence suggests that the overall prevalence of GJB2 variants is similar around the world, although specific variants differ.12 Variants in the GJB6 gene lead to similar effects on abnormal expression of connexin protein Cx30. However, GJB6 variants are much less common than variants in GJB2. Of all the patients with hereditary hearing loss, approximately 3% are found to have a mutation in the GJB6 gene.

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Table 1. Clinical Characteristics and Testing Methods for GJB2 and GJB6 Variants at the DFNA3 and DFNB1 Loci Locus

Gene

Name

Symbol

DFNA3

GJB2

Onset

Audioprofile

Test Method

Variants Detected

Prelingual

High -frequency

Sequence Analysis/ Mutation

Sequence Variants

progressive

Scanning

Specified sequence

Targeted mutation analysis

variants

Deletion/duplication analysis

Exonic or whole-gene deletions/duplications

DFNA3

GJB6

Prelingual

High-frequency

Sequence Analysis/ Mutation

Sequence Variants

progressive

Scanning Targeted Mutation

Specified sequence

Analysis

variants

Deletion/ duplication analysis

Exonic or whole-gene deletions/duplications

DFNB1

DFNB1

GJB2

GJB6

Prelingual

Prelingual

Usually stable

Usually stable

Targeted mutation analysis

GJB2 sequence variants

Deletion/ duplication analysis

Exon(s) or whole-gene

4

deletions

Deletion/ duplication analysis

GJB6 deletions

Analysis for GJB6 and GJB2 variants 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 1 gene at a time. With Sanger sequencing, the gene with the most common variants is generally sequenced first, followed by sequencing of additional genes if a pathogenic mutation is not found. In addition to the most common variants in genes that are associated with hereditary hearing loss, GJB6 and GJB2, there are many less common pathologic variants. Some of these genes 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. Novel genetic variants continue to be identified in cases of hereditary hearing loss.13,14 As of 2014, over 2,000 pathogenic deafness variants in approximately 130 genes had been reported.15,16 In contrast, only 18 pathogenic copy number variants (CNVs) had been identified by 2014.17 CNVs, caused by insertions, deletions, or recombination, can lead to hearing loss from gene disruption or changes in the number of dose-sensitive genes. The gene most commonly associated with

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pathogenic CNVs in hearing loss is STRC, which encodes stereocilin and is the most frequent cause of autosomal recessive causes of NSHL after variants in GJB2.17 Because of the large number of genes associated with hereditary hearing loss, 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 2. 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. In addition, whole exome sequencing and whole genome sequencing have been used to identify novel variants in subjects with a history suggestive of genetic hereditary hearing loss.18-20 Targeted genomic enrichment coupled with massively parallel sequencing can be used to identify both single nucleotide variants and CNVs.

Table 2. Gene Panels for Hereditary Hearing Loss11 Test

Technology

Partners Healthcare

Next generation

(OtoGenome™ Test for Hearing

sequencing, followed

Loss and Related Syndromes)

by confirmation with

Genes Tested;

Analytic

Variants Tested

Sensitivity, %

87; NA

99%

116; NA

99%

Sanger sequencing or PCR University of Iowa Healthcare (OtoSCOPE® V6)

21

Next generation/Massive parallel sequencing

NGS: next-generation sequencing; PCR: polymerase chain reaction.

Overlap Between NSHL and Recognized Syndromes There is overlap between hereditary NSHL and hearing loss associated with recognized syndromes. Some genetic variants may be associated with clinical findings other than hearing loss, but they are not necessarily present at the time of presentation with hearing loss. For example, Jervell and Lange-Nielsen syndrome is associated with congenital deafness and prolonged QT interval, but it may present only with deafness without an apparent history to suggest cardiac dysfunction. Additionally, some of the genes associated with NSHL are also

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associated with recognized syndromes. A summary of some of the genetic syndromes and variants that may have overlap with NSHL is shown in Table 3.

Table 3. Genes With Overlap Between Syndromic and Nonsyndromic Hearing Loss Syndrome Usher syndrome

Inheritance

Clinical

Gene

Reason for Overlap

Description

Mutation(s)

With NSHL

For all types:

For all types:

Retinitis pigmentosa usually

autosomal

sensorineural hearing

not apparent in 1st decade

recessive

loss with retinitis pigmentosa

Type 1

Congenital severe-to-

MYO7A USH1C

DFNB18 (nonsyndromic) may

profound hearing loss

CDH23 PCDH15

also be caused by variants in

SANS CIB2

USH1C

Abnormal vestibular function

DFNB12 (nonsyndromic) may also be caused by variants in CDH23 DFNB2 (nonsyndromic) and DFNA11 (nonsyndromic) may also be caused by variants in MYO7A

Type 2

Congenital mild-to-

USH2A VLGR1

severe hearing loss

WHRN

Normal vestibular function Type 3

Progressive hearing loss

CLRN1i PDZD7

Progressive vestibular dysfunction Pendred

Autosomal

Congenital sensorineural

syndrome

recessive

hearing loss

SLC26A4 (50%)

Goiter not present until early puberty or adulthood.

Bony labyrinth

Variants in SLC26A4 may also

abnormalities (Mondini

cause NSHL

dysplasia or dilated vestibular aqueduct) Euthyroid goiter Jervell and

Autosomal

Congenital deafness

Lange-Nielsen

KCNQ1 KCNE1

Hearing loss may present without personal or family

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Syndrome syndrome

Inheritance recessive

Clinical

Gene

Reason for Overlap

Description

Mutation(s)

With NSHL

Prolongation of the QT

history of cardiac symptoms

interval

(sudden death, SIDS, syncopal episodes, or long QT syndrome)

Wolfram

Autosomal

Progressive sensorineural

syndrome

recessive

hearing loss Diabetes mellitus Optic atrophy

WFS1

WFS1-associated hearing loss (DFNA6/14/38; congenital hearing loss without associated findings) may also be caused by variants in WFS1

Progressive neurologic abnormalities SIDS: sudden infant death syndrome.

Summary of Evidence For individuals who are suspected of having hereditary nonsyndromic hearing loss (NSHL) who receive genetic testing, the evidence includes small retrospective, single-center studies, case reports, case series, and genotype-phenotype correlation studies evaluating the clinical validity and genetic testing yield for NSHL. Relevant outcomes are test accuracy and validity, changes in reproductive decision making, morbid events, and resource utilization. Genetic variants in GJB2, GJB6, and numerous other genes are found in a substantial percentage of patients with hereditary hearing loss. The analytic validity of genetic testing for hereditary hearing loss is high. Of all patients with suspected hereditary hearing loss after clinical examination, a substantial proportion, in the range of 30% to 60%, will be found to have a genetic variant. The probability of finding a genetic variant is increasing as new gene variants are identified. False-positive results on genetic testing are expected to be very low. For diagnosis, there are a number of potential benefits of genetic testing, including a reduction in the need for alternative diagnostic tests and monitoring of patients with genetically identified syndromic hearing loss associated with other medical conditions. Clinical guidelines have recommended a tiered genetic testing approach, starting with the most common genes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. For individuals with a family history of hereditary NSHL who receive preconception genetic testing to determine carrier status, the evidence is limited but includes clinical guidelines. Relevant outcomes are test accuracy and validity, changes in reproductive decision making, morbid events, and resource utilization. Genetic variants in GJB2, GJB6, and numerous other

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genes are found in a substantial percentage of patients with hereditary hearing loss. The analytic validity of genetic testing for hereditary hearing loss is high. The probability of finding a genetic variant is increasing as new gene variants are identified. False-positive results on genetic testing are expected to be very low. There are several situations for which there is potential clinical utility of testing for genes associated with hereditary hearing loss. For parents at high risk of an offspring with hereditary hearing loss, genetic testing can be useful as an aid in reproductive decision making. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Ongoing and Unpublished Clinical Trials Some currently unpublished trials that might influence this review are listed in Table 4.

Table 4. Summary of Key Trials NCT No.

Trial Name

Planned

Completion

Enrollment

Date

Long QT & Hearing Loss Prospective Study Registry

600

Aug 2018

Prevalence of POU4F3 (DFNA15) and SLC17A8

150

Terminated

Ongoing NCT02082431

Unpublished NCT01802190

(DFNA25) Genes Mutations in Dominant Autosomal Deafness and Phenotypic Characterization of Carrier Patients

“no convincing results”

NCT: national clinical trial.

Clinical Input Received from Physician Specialty Societies and Academic Medical Centers While the various physician specialty societies and academic medical centers may provide appropriate reviewers who collaborate with and make recommendations during this process, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

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In response to requests, input was received from two physician specialty societies and 2 academic medical centers while this policy was under review in 2013. Reviewers agreed with the medically necessary indication for carrier testing, and with additional indications for carrier testing. There was support for testing the index case to confirm NSHL among a majority of reviewers. Reviewers in favor of genetic testing cited the ability to distinguish NSHL from other causes of hearing loss, to streamline the diagnostic workup and avoid further unnecessary testing and to provide referrals to specialists when specific types of variants were identified that are associated with disorders in other organ systems. It was considered that two contextual factors were present: barriers to performing high-quality trials, and the potential to reduce harms by avoiding unnecessary testing.

Practice Guidelines and Position Statements

American College of Medical Genetics and Genomics In 2014, the American College of Medical Genetics and Genomics issued a practice guideline37 for the clinical evaluation and etiologic diagnosis of hearing loss. The guideline recommends obtaining testing for acquired hearing loss if there is clinical suspicion, including testing for cytomegalovirus (CMV), imaging, or other testing based on the suspected etiology. For individuals lacking physical findings suggestive of a known syndrome and having medical and birth histories that do not suggest an environmental cause of hearing loss, the guidelines make the following recommendations for a tiered diagnostic approach: 

Pretest genetic counseling should be provided, and, with patient’s informed consent, genetic testing should be ordered. o

Single-gene testing may be warranted in cases in which the medical or family history, or presentation of the hearing loss, suggests a specific etiology. For example, testing for mitochondrial DNA mutations associated with aminoglycoside ototoxicity may be considered for individuals with a history of use of aminoglycoside antibiotics.

o

In the absence of any specific clinical indications and for singleton cases and cases with apparent autosomal recessive inheritance, the next step should be testing for DFNB1related hearing loss (due to mutations in GJB2 and adjacent deletions in GJB6).

o

If initial genetic testing is negative, genetic testing using gene panel tests, NGS technologies such as large sequencing panels targeted toward hearing loss–related genes, whole exome sequencing, or whole genome sequencing may be considered. Because several tests are clinically available, the clinician must be aware of the genes

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included in the test (panel) chosen and the performance characteristics of the platform chosen, including coverage, analytic sensitivity, and what types of mutations will be detected. o

If genetic testing reveals mutation(s) in a hearing loss–related gene, mutation-specific genetic counseling should be provided, followed by appropriate medical evaluations and referrals.

American Academy of Pediatrics The American Academy of Pediatrics (AAP) issued recommendations on early hearing detection in 200736: Every infant with confirmed hearing loss and/or middle ear dysfunction should be referred for otologic and other medical evaluation. The purpose of these evaluations is to determine the etiology of hearing loss, to identify related physical conditions, and to provide recommendations for medical/surgical treatment as well as referral for other services. Essential components of the medical evaluation include clinical history, family history of childhood-onset permanent hearing loss, identification of syndromes associated with earlyor late-onset permanent hearing loss, a physical examination, and indicated radiologic and laboratory studies (including genetic testing). The evaluation, therefore, should include a review of family history of specific genetic disorders or syndromes, including genetic testing for gene mutations such as GJB2 (connexin-26), and syndromes commonly associated with early-onset childhood sensorineural hearing loss…. All families of children with confirmed hearing loss should be offered, and may benefit from, a genetics evaluation and counseling. This evaluation can provide families with information on etiology of hearing loss, prognosis for progression, associated disorders (eg, renal, vision, cardiac), and likelihood of recurrence in future offspring. This information may influence parents' decision-making regarding intervention options for their child. There is a 2013 supplement to AAP’s 2007 position statement on early intervention after confirmation that a child is deaf or hard of hearing.37 Genetic testing was not addressed.

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Medicare National Coverage There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.

Regulatory Status Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Molecular diagnostic testing is available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of these tests.

References

1.

Smith RJH, Shearer AE, Hildebrand MS, et al. Deafness and Hereditary Hearing Loss Overview. GeneReviews. 2014. PMID 20301607

2.

Morton CC, Nance WE. Newborn hearing screening--a silent revolution. N Engl J Med. May 18 2006;354(20):2151-2164. PMID 16707752

3.

Matsunaga T. Value of genetic testing in the otological approach for sensorineural hearing loss. Keio J Med. Dec 2009;58(4):216-222. PMID 20037285

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. May-Jun 2002;4(3):162-171. PMID 12180152

5.

Milunsky JM, Maher TA, Yosunkaya E, et al. Connexin-26 gene analysis in hearing-impaired newborns. Genet Test. 2000;4(4):345-349. PMID 11216657

6.

Smith RJH, Ranum PT. Nonsyndromic Hearing Loss and Deafness, DFNA3. GeneReviews. 2016. PMID 20301708

7.

Smith RJH, Jones MKN. Nonsyndromic Hearing Loss and Deafness, DFNB1. GeneReviews. 2016. PMID 20301449

8.

Apps SA, Rankin WA, Kurmis AP. Connexin 26 mutations in autosomal recessive deafness disorders: a review. Int J Audiol. Feb 2007;46(2):75-81. PMID 17365058

9.

Green GE, Scott DA, McDonald JM, et al. Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness. JAMA. Jun 16 1999;281(23):2211-2216. PMID 10376574

10. Bitner-Glindzicz M. Hereditary deafness and phenotyping in humans. Br Med Bull. 2002;63:73-94. PMID 12324385 11. 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. Feb 2013;52(2):124-133. PMID 23131088

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12. Chan DK, Chang KW. GJB2-associated hearing loss: systematic review of worldwide prevalence, genotype, and auditory phenotype. Laryngoscope. Feb 2014;124(2):E34-53. PMID 23900770 13. Azaiez H, Booth KT, Bu F, et al. TBC1D24 mutation causes autosomal-dominant nonsyndromic hearing loss. Hum Mutat. Jul 2014;35(7):819-823. PMID 24729539 14. Goncalves AC, Matos TD, Simoes-Teixeira HR, et al. WFS1 and non-syndromic low-frequency sensorineural hearing loss: a novel mutation in a Portuguese case. Gene. Apr 1 2014;538(2):288-291. PMID 24462758 15. Shearer AE, Eppsteiner RW, Booth KT, et al. Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants. Am J Hum Genet. Oct 2 2014;95(4):445-453. PMID 25262649 16. Vona B, Muller T, Nanda I, et al. Targeted next-generation sequencing of deafness genes in hearing-impaired individuals uncovers informative mutations. Genet Med. Dec 2014;16(12):945-953. PMID 24875298 17. Shearer AE, Kolbe DL, Azaiez H, et al. Copy number variants are a common cause of non-syndromic hearing loss. Genome Med. 2014;6(5):37. PMID 24963352 18. Choi BY, Kim J, Chung J, et al. Whole-exome sequencing identifies a novel genotype-phenotype correlation in the entactin domain of the known deafness gene TECTA. PLoS One. 2014;9(5):e97040. PMID 24816743 19. Kim HJ, Won HH, Park KJ, et al. SNP linkage analysis and whole exome sequencing identify a novel POU4F3 mutation in autosomal dominant late-onset nonsyndromic hearing loss (DFNA15). PLoS One. 2013;8(11):e79063. PMID 24260153 20. Bademci G, Diaz-Horta O, Guo S, et al. Identification of copy number variants through whole-exome sequencing in autosomal recessive nonsyndromic hearing loss. Genet Test Mol Biomarkers. Sep 2014;18(9):658-661. PMID 25062256 21. University of Iowa. Otoscope Genetic Testing. 2015; https://morl.lab.uiowa.edu/otoscope-genetic-testing Accessed June 2017. 22. Siemering K, Manji SS, Hutchison WM, et al. Detection of mutations in genes associated with hearing loss using a microarraybased approach. J Mol Diagn. Sep 2006;8(4):483-489; quiz 528. PMID 16931589 23. 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. Feb 2008;29(2):306-314. PMID 18161878 24. Abe S, Yamaguchi T, Usami S. Application of deafness diagnostic screening panel based on deafness mutation/gene database using invader assay. Genet Test. Fall 2007;11(3):333-340. PMID 17949297 25. 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. Sep 2006;118(3):985-994. PMID 16950989 26. Kothiyal P, Cox S, Ebert J, et al. High-throughput detection of mutations responsible for childhood hearing loss using resequencing microarrays. BMC Biotechnol. 2010;10:10. PMID 20146813 27. Gu X, Guo L, Ji H, et al. Genetic testing for sporadic hearing loss using targeted massively parallel sequencing identifies 10 novel mutations. Clin Genet. Jun 2015;87(6):588-593. PMID 24853665 28. Fukushima K, Sugata K, Kasai N, et al. Better speech performance in cochlear implant patients with GJB2-related deafness. Int J Pediatr Otorhinolaryngol. Feb 1 2002;62(2):151-157. PMID 11788148 29. Matsushiro N, Doi K, Fuse Y, et al. Successful cochlear implantation in prelingual profound deafness resulting from the common 233delC mutation of the GJB2 gene in the Japanese. Laryngoscope. Feb 2002;112(2):255-261. PMID 11889380 30. Popov TM, Stancheva I, Kachakova DL, et al. Auditory outcome after cochlear implantation in patients with congenital nonsyndromic hearing loss: influence of the GJB2 status. Otol Neurotol. Sep 2014;35(8):1361-1365. PMID 24691507 31. Yan YJ, Li Y, Yang T, et al. The effect of GJB2 and SLC26A4 gene mutations on rehabilitative outcomes in pediatric cochlear implant patients. Eur Arch Otorhinolaryngol. Nov 2013;270(11):2865-2870. PMID 23296490 32. Sinnathuray AR, Toner JG, Clarke-Lyttle J, et al. Connexin 26 (GJB2) gene-related deafness and speech intelligibility after cochlear implantation. Otol Neurotol. Nov 2004;25(6):935-942. PMID 15547423

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33. Sinnathuray AR, Toner JG, Geddis A, et al. Auditory perception and speech discrimination after cochlear implantation in patients with connexin 26 (GJB2) gene-related deafness. Otol Neurotol. Nov 2004;25(6):930-934. PMID 15547422 34. Connell SS, Angeli SI, Suarez H, et al. Performance after cochlear implantation in DFNB1 patients. Otolaryngol Head Neck Surg. Oct 2007;137(4):596-602. PMID 17903576 35. Alford RL, Arnos KS, Fox M, et al. American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss. Genet Med. Apr 2014;16(4):347-355. PMID 24651602 36. American Academy of Pediatrics Joint Committee on Infant Hearing. Year 2007 position statement: Principles and guidelines for early hearing detection and intervention programs. Pediatrics. Oct 2007;120(4):898-921. PMID 17908777 37. Joint Committee on Infant Hearing of the American Academy of Pediatrics, Muse C, Harrison J, et al. Supplement to the JCIH 2007 position statement: principles and guidelines for early intervention after confirmation that a child is deaf or hard of hearing. Pediatrics. Apr 2013;131(4):e1324-1349. PMID 23530178

History

Date

Comments

11/11/13

New Policy. Policy created with literature search through June 30, 2013 and clinical input reviewed; may be considered medically necessary for confirmation of the diagnosis of hereditary nonsyndromic hearing loss, and for carrier testing in parents under certain conditions.

11/20/14

Annual Review. Policy title and policy statements changed to refer to “hereditary hearing loss” (from “nonsyndromic hearing loss”) to reflect significant overlap between nonsyndromic and syndromic hearing loss. Added related policy 12.04.92 General Approach to Evaluating the Utility of Genetic Panels. Added Table 2 - a summary of some of the genetic syndromes and variants that may have overlap with NSHL. Replaced the word “proband” with “index patient”. Policy updated with literature review through July 29, 2014. References 3, 10-11, 17-22, 36, 37, 40-41, 45-48 added. Policy statements changed as noted. New CPT code 81430 added effective 1/15.

01/14/15

Coding update. New CPT code 81431, effective 1/1/15, added to policy. Update related policy title 7.01.105.

11/10/15

Annual Review. Policy updated with literature review through September 17, 2015; references 15-17 added. Policy statement unchanged.

12/01/16

Annual review, approved November 8, 2016. No change to policy statement. No references added.

07/01/17

Annual Review, approved June 6, 2017. Policy moved into new format. Policy updated with literature review through February 23, 2017; no references added, references 3536 removed due to unselected pediatric population for genetic testing. The policy is revised with updated genetics nomenclature. “Mutations” changed to “variants” in policy statements; statements otherwise unchanged.

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Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). ©2017 Premera All Rights Reserved. Scope: Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

Page | 18 of 18



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037336 (07-2016)

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ໝັ ກ ຫື ຼ ຄວາມຄຸ້ ມຄອງປະກັ ນໄພຂອງທ່ ານຜ່ ານ LifeWise Health Plan of Washington. ອາດຈະມີວັ ນທີສໍາຄັ ນໃນແຈ້ ງການນ້ີ . ທ່ ານອາດຈະຈໍາເປັນຕ້ ອງດໍາ ເນີນການຕາມກໍານົ ດເວລາສະເພາະເພື່ອຮັ ກສາຄວາມຄຸ້ ມຄອງປະກັ ນສຸ ຂະພາບ ຫື ຼ ຄວາມຊ່ ວຍເຫື ຼ ອເລື່ອງຄ່ າໃຊ້ ຈ່ າຍຂອງທ່ ານໄວ້ . ທ່ ານມີສິດໄດ້ ຮັ ບຂໍ້ມູ ນນີ້ ແລະ ຄວາມ ຊ່ ວຍເຫື ຼ ອເປັນພາສາຂອງທ່ ານໂດຍບໍ່ເສຍຄ່ າ. ໃຫ້ ໂທຫາ 800-592-6804 (TTY: 800-842-5357). ភាសាែខម រ (Khmer): េសចកត ីជូនដំណឹងេនះមានព័ត៌មានយា៉ងសំខាន់។ េសចកត ីជូនដំណឹងេនះរបែហល ជាមានព័ត៌មានយា៉ងសំខាន់អំពីទរមង់ែបបបទ ឬការរា៉ប់រងរបស់អនកតាមរយៈ LifeWise Health Plan of Washington ។ របែហលជាមាន កាលបរ ិេចឆ ទសំខាន់េនៅ កនុងេសចកត ីជូនដំណឹងេនះ។ អន ករបែហលជារតូវការបេញច ញសមតថ ភាព ដល់កំណត់ ៃថង ជាក់ចបាស់នានា េដើមបីនឹងរកសាទុកការធានារា៉ប់រងសុខភាពរបស់អនក ឬរបាក់ ជំនួយេចញៃថល ។ អន កមានសិទធិទទួ លព័ត៌មានេនះ និងជំនួយេនៅកនុងភាសារបស់អនក េដាយមិនអសលុយេឡើយ។ សូ មទូ រស័ពទ 800-592-6804 (TTY: 800-842-5357)។ ਪੰ ਜਾਬੀ (Punjabi): ਇਸ ਨੋਿਟਸ ਿਵਚ ਖਾਸ ਜਾਣਕਾਰੀ ਹੈ. ਇਸ ਨੋਿਟਸ ਿਵਚ LifeWise Health Plan of Washington ਵਲ ਤੁਹਾਡੀ ਕਵਰੇਜ ਅਤੇ ਅਰਜੀ ਬਾਰੇ ਮਹੱ ਤਵਪੂਰਨ ਜਾਣਕਾਰੀ ਹੋ ਸਕਦੀ ਹੈ . ਇਸ ਨੋਿਜਸ ਜਵਚ ਖਾਸ ਤਾਰੀਖਾ ਹੋ ਸਕਦੀਆਂ ਹਨ. ਜੇਕਰ ਤੁਸੀ ਜਸਹਤ ਕਵਰੇਜ ਿਰੱ ਖਣੀ ਹੋਵੇ ਜਾ ਓਸ ਦੀ ਲਾਗਤ ਜਿਵੱ ਚ ਮਦਦ ਦੇ ਇਛੁੱ ਕ ਹੋ ਤਾਂ ਤੁਹਾਨੂੰ ਅੰ ਤਮ ਤਾਰੀਖ਼ ਤ ਪਿਹਲਾਂ ਕੁੱ ਝ ਖਾਸ ਕਦਮ ਚੁੱ ਕਣ ਦੀ ਲੋ ੜ ਹੋ ਸਕਦੀ ਹੈ ,ਤੁਹਾਨੂੰ ਮੁਫ਼ਤ ਿਵੱ ਚ ਤੇ ਆਪਣੀ ਭਾਸ਼ਾ ਿਵੱ ਚ ਜਾਣਕਾਰੀ ਅਤੇ ਮਦਦ ਪ੍ਰਾਪਤ ਕਰਨ ਦਾ ਅਿਧਕਾਰ ਹੈ ,ਕਾਲ 800-592-6804 (TTY: 800-842-5357).

‫( فارسی‬Farsi): ‫اين اعالميه ممکن است حاوی اطالعات مھم درباره فرم‬. ‫اين اعالميه حاوی اطالعات مھم ميباشد‬ ‫ به‬.‫ باشد‬LifeWise Health Plan of Washington ‫تقاضا و يا پوشش بيمه ای شما از طريق‬ ‫شما ممکن است برای حقظ پوشش بيمه تان يا کمک‬. ‫تاريخ ھای مھم در اين اعالميه توجه نماييد‬ ‫ به تاريخ ھای مشخصی برای انجام کارھای خاصی احتياج‬،‫در پرداخت ھزينه ھای درمانی تان‬ ‫شما حق اين را داريد که اين اطالعات و کمک را به زبان خود به طور رايگان‬. ‫داشته باشيد‬ 800-592-6804 ‫ برای کسب اطالعات با شماره‬.‫دريافت نماييد‬ .‫( تماس برقرار نماييد‬800-842-5357 ‫ تماس باشماره‬TTY ‫)کاربران‬ Polskie (Polish): To ogłoszenie może zawierać ważne informacje. To ogłoszenie może zawierać ważne informacje odnośnie Państwa wniosku lub zakresu świadczeń poprzez LifeWise Health Plan of Washington. Prosimy zwrócic uwagę na kluczowe daty, które mogą być zawarte w tym ogłoszeniu aby nie przekroczyć terminów w przypadku utrzymania polisy ubezpieczeniowej lub pomocy związanej z kosztami. Macie Państwo prawo do bezpłatnej informacji we własnym języku. Zadzwońcie pod 800-592-6804 (TTY: 800-842-5357). Português (Portuguese): Este aviso contém informações importantes. Este aviso poderá conter informações importantes a respeito de sua aplicação ou cobertura por meio do LifeWise Health Plan of Washington. Poderão existir datas importantes neste aviso. Talvez seja necessário que você tome providências dentro de determinados prazos para manter sua cobertura de saúde ou ajuda de custos. Você tem o direito de obter esta informação e ajuda em seu idioma e sem custos. Ligue para 800-592-6804 (TTY: 800-842-5357).

Español (Spanish): Este Aviso contiene información importante. Es posible que este aviso contenga información importante acerca de su solicitud o cobertura a través de LifeWise Health Plan of Washington. Es posible que haya fechas clave en este aviso. Es posible que deba tomar alguna medida antes de determinadas fechas para mantener su cobertura médica o ayuda con los costos. Usted tiene derecho a recibir esta información y ayuda en su idioma sin costo alguno. Llame al 800-592-6804 (TTY: 800-842-5357). Tagalog (Tagalog): Ang Paunawa na ito ay naglalaman ng mahalagang impormasyon. Ang paunawa na ito ay maaaring naglalaman ng mahalagang impormasyon tungkol sa iyong aplikasyon o pagsakop sa pamamagitan ng LifeWise Health Plan of Washington. Maaaring may mga mahalagang petsa dito sa paunawa. Maaring mangailangan ka na magsagawa ng hakbang sa ilang mga itinakdang panahon upang mapanatili ang iyong pagsakop sa kalusugan o tulong na walang gastos. May karapatan ka na makakuha ng ganitong impormasyon at tulong sa iyong wika ng walang gastos. Tumawag sa 800-592-6804 (TTY: 800-842-5357).

ไทย (Thai): ประกาศนี ้มีข้อมูลสําคัญ ประกาศนี ้อาจมีข้อมูลที่สําคัญเกี่ยวกับการการสมัครหรื อขอบเขตประกัน สุขภาพของคุณผ่าน LifeWise Health Plan of Washington และอาจมีกําหนดการในประกาศ นี ้ คุณอาจจะต้ องดําเนินการภายในกําหนดระยะเวลาที่แน่นอนเพื่อจะรักษาการประกันสุขภาพของคุณ หรื อการช่วยเหลือที่มีค่าใช้ จ่าย คุณมีสิทธิที่จะได้ รับข้ อมูลและความช่วยเหลือนี ้ในภาษาของคุณโดยไม่มี ค่าใช้ จ่าย โทร 800-592-6804 (TTY: 800-842-5357) Український (Ukrainian): Це повідомлення містить важливу інформацію. Це повідомлення може містити важливу інформацію про Ваше звернення щодо страхувального покриття через LifeWise Health Plan of Washington. Зверніть увагу на ключові дати, які можуть бути вказані у цьому повідомленні. Існує імовірність того, що Вам треба буде здійснити певні кроки у конкретні кінцеві строки для того, щоб зберегти Ваше медичне страхування або отримати фінансову допомогу. У Вас є право на отримання цієї інформації та допомоги безкоштовно на Вашій рідній мові. Дзвоніть за номером телефону 800-592-6804 (TTY: 800-842-5357). Tiếng Việt (Vietnamese): Thông báo này cung cấp thông tin quan trọng. Thông báo này có thông tin quan trọng về đơn xin tham gia hoặc hợp đồng bảo hiểm của quý vị qua chương trình LifeWise Health Plan of Washington. Xin xem ngày quan trọng trong thông báo này. Quý vị có thể phải thực hiện theo thông báo đúng trong thời hạn để duy trì bảo hiểm sức khỏe hoặc được trợ giúp thêm về chi phí. Quý vị có quyền được biết thông tin này và được trợ giúp bằng ngôn ngữ của mình miễn phí. Xin gọi số 800-592-6804 (TTY: 800-842-5357).