CAM 20487

Genetic Testing for Hereditary Hearing Loss

Category:Laboratory   Last Reviewed:July 2019
Department(s):Medical Affairs   Next Review:July 2020
Original Date:December 2014    

Description
Hearing loss is among the most etiologically heterogeneous disorders, with more than 400 genetic syndromes that include hearing loss as a feature, more than 100 genes associated with nonsyndromic genetic hearing loss and a number of non-genetic causes.  Genes associated with syndromic and nonsyndromic genetic hearing loss encode a variety of proteins involved in the development and function of the auditory system, including transcription factors, structural proteins, gap junction proteins and ion channels (ACMG, 2014). The genes may be associated with an autosomal dominant, autosomal recessive, X­ linked or mitochondria l inheritance pattern.

Background
Approximately one in every 500 children born in the United States is deaf or has a hearing loss significant enough to affect speech and language development. Ninety-five percent of newborns with hearing loss identified by newborn hearing screening programs are born to hearing parents, obscuring the fact that the majority of newborns have a hereditary cause for their  hearing loss (ACMG, 2014). 

Hearing loss is typically described in terms related to its clinical presentation. In general, it is categorized as either syndromic or nonsyndromic. Syndromic hearing loss is associated with other medical or physical findings, including malformations of the external ear or other organs or with medical problems involving other organ systems. An estimated 30% of hereditary hearing loss is syndromic. As diagnosis of these syndromes is generally made based on an indivdual's constellation or symptoms or abnormalities,  genetic testing for syndromic hearing loss is outside the scope of this policy. Nonsyndronomic hearing loss (NSHL) is defined as hearing loss that is not associated with visible abnormalities of the external ear or any related medical problems. For NSHL, it is more difficult to determine whether the etiology is hereditary or acquired, because there are no other clinical manifestations at the time of the hearing loss presentation. NSHL accounts for an estimated 70% of genetically determined hearing loss. 

Approximately 80 percent of cases of hereditary hearing loss are inherited in an autosomal recessive pattern, 15 percent are autosomal dominant, 2 percent are X-linked (mainly recessive) and 1 percent are mitochondrial. 

A typical clinical presentation of autosomal recessive NSHL involves the following characteristics:

  • Sensorineural hearing loss
  • Mild to profound degree of hearing impairment
  • Usually present at birth
  • Typically, bilateral and non-progressive
  • No associated abnormalities or related medical problems 

The genetic loci on which mutations associated with nonsyndromic hereditary hearing loss are usually found are termed DFN. 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. The DFNBl locus, which includes the GJB2 gene encoding the gap junction protein connexin 26 and the GJB6 gene encoding the gap junction protein connexin 30, account for an estimated 50% of all autosomal recessive nonsyndromic hearing loss and 15-40% of all deaf individuals in a variety of populations. 

GJB2 is a small gene with a single coding exon. More than 150 deafness-causing variants have been identified in GJB2, but a few cqmmon mutations account for a large percentage of alleles in several populations. Mutations in the GJB2 gene impact expression of the Cx26 connexin  protein  and  almost  always  cause  prelingual, but  not  necessarily  congenital, deafness. It is therefore possible that hearing may be normal at birth and then deteriorate rapidly during the first few months of life, although this is rare. Mutations in the GJB6 gene lead to similar effects on abnormal expression of connexin protein Cx30. GJB6 deletions have  been  observed  in  multiple  populations,  although they  appear  to  be  a  relatively uncommon  explanation  for  hearing  loss  in the  United  States.  Of  all the  patients  with hereditary hearing loss, approximately 3% are found to have a mutation in the GJB6 gene. 

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: ACTGl, BSND, CDH23, CLDN14, COCH, COL11A2, DFNA5, DFNB31, DFNB59, ESPN, ESRRB, EYA4, GRXCRl, HGF, KCNQ4,  LHFPLS,  MARVELD2,  MT-TSl, MYOlSA,  MY06, MY07A,  OTOA,  OTOF,  PCDHlS, POU3F4, PTPRQ, RDX, SLC26A4, STRC, TECTA, TMCl, TMIE, TMPRSS3, TR IOBP, USHlC, WFSl and WHRN genes (Smith et al., 2014).

Evaluation of a patient with suspected hereditary  hearing loss should include a comprehensive prenatal, neonatal and postnatal history, as well as a three-generation family history. A thorough physical exam, with particular attention to ear structure and other craniofacial anomalies, dysmorphic features, delayed developmental milestones to assess for  associated clinical findings that may point to a specific syndrome or acquired nonsyndromic cause of hearing loss (e.g., infectious, toxic, autoimmune, age-related or other causes), should be completed. Consideration should also be given to audiometric assessment, temporal bone computed tomography scanning in cases of progressive hearing loss and testing for cytomegalovirus (CMV) in infants with sensorineural hearing loss. 

The extreme genetic heterogeneity and the frequent lack of phenotypic variability make genetic diagnosis of NSHL difficult using single-gene screening techniques (Smith et al., 2014). For this reason, several groups have developed multi-gene screening panels for NSHL. It is important to note that these screening panels vary by laboratory both in the techniques used and the number of genes sequenced. Some laboratories target only reported deafness­-causing variants in several genes, while other laboratories sequence all genes implicated in NSHL. It is likely that as such tests become more widespread, the management of genetic hearing loss will change to a single comprehensive genetic test for all types of hearing loss. 

When initial gene testing is being considered for nonsyndromic hereditary hearing loss after thorough evaluation as listed above, molecular genetic testing of GJB2 (which encodes the protein connexin 26) and GJB6 (which encodes the protein connexin 30) should be considered in the evaluation of individuals with congenital nonsyndromic sensorineural hearing loss consistent with autosomal recessive inheritance or in families with apparent "pseudodominant" inheritance of DFNBl. Pseudodominant inheritance refers to occurrence of an autosomal recessive disorder in two or more generations of a family; such inheritance tends to occur when the carrier rate in the general population is high. GJB2 and GJB6 molecular genetic testing should be performed in families with nonsyndromic hearing loss in which two generations are involved. If negative, prioritization of genes for testing can be based on clinical features (age at presentation, audioprofile) or pattern of inheritance (e.g., autosomal recessive).  A summary of possible genes related to nonsyndromic hereditary hearing loss is found in tables 1-3 below, as excepted from the American College of Medical Genetics and Genomics (2014).

Table  1.  Clinical  Manifestations   and  Molecular Genetics of Known Genes Causing Autosomal Dominant Nonsyndromic Hearing Impairment

Locus

Gene 

Onset/Decade 

Audioprofile 

DFNAl
DFNA2
DFNA2B
DFNA3
DNFA3
DFNA4
DFNAS
DFNA6/14/38
DFNA8/12
DFNA9
DFNAlO
DFNAll
DFNA13
DFNAlS
DFNA17
DFNA20/26
DFNA22
DFNA23
DFNA25
DFNA28
DFNA36
DFNA 39
DFNA41
DFNA44
DFNA48
DFNASO
DFNASl
DFNASl

DIAPHl
KCNQ4
GJB3
GJB2
GJB6
MYH14
DFNAS
WFSl T
ECTA
COCH
EYA4
MY07A
COL11A2
POU4F3
MYH9
ACTGl
MY06
SIXl
SLC17A8
GRHL2
TMCl
DSPP
P2RX2
CCDCSO
MYOlA  P
MIR96
TJP2
FAM189A2

Postlingual/st
Postlingual/2nd
Postlingual/4th
Prelingual
Prelingual
Postlingual
Postlingual/lst
Prelingual
Prelingual
Postlingual/2nd
Postlingual/3rd, 4th
Postlingual/lst
Postlingual/2"d
Postlingual
Postlingual
Postlingual
Postlingual
Prelingual
Postlingual/1-6decades
Postlingual
Postlingual
Postlingual
Postlingual
Postlingual
Postlingual
Postlingual/2nd
Postlingual/4th
Postlingual/4'h

Low frequency progressive
High frequency progressive
High frequency progressive
High frequency progressive
High frequency progressive
Flat/gently downsloping
High frequency progressive
Low frequency progressive
Mid-frequency loss
High frequency progressive
Flat/gently downsloping

Mid-frequency loss
High frequency progressive
High frequency progressive
High frequency progressive
High frequency progressive
Downsloping
High frequency progressive
Flat/gently downsloping
Flat/gently downsloping
High frequency progressive
Flat progressive
Low to mild frequencies prog.
Progressive
Flat progressive
High frequency progressive
High frequency progressive

Adapted from Van Camp & Smith [2010]
See Deafness, Autosomal Dominant: Phenotypic Series to view genes associated with this phenotype  in OMIM.

Table  2.  Clinical  Manifestations  and  Molecular  Genetics  of   Known  Genes  Causing Autosomal  Recessive Nonsyndromic Hearing Impairment

Locus Gene Onset Type
DFNBl GJB2  Prelingual 1 Usually Stable 
DFNBl GJB6  Prelingual Usually Stable 
DFNB2 MY07A  Prelingual/Postlingual Unspecified 
DFNB3 MYOlSA  Prelingual Severe to profound; stable 
DFNB4 SLC26A4  Prelingual/Postingual Stable,progressive 
DFNB6 TMIE Prelingual Severe to profound;stable 
DFNB7/11 TMCl  Prelingual Severe to profound; stable 
DFNB8/10 TMPRSS3  Prelingual 2/Prelingual Progressive,stable 
DFNB9 OTOF  Prelingual Severe to profound; stable 
DFNB12 CDH23  Prelingual Severe to profound; stable  
DFNB16 STRC  Prelingual Severe to profound; stable  
DFNB18 USHlC  Prelingual Severe to profound; stable  
DFNB21 TECTA  Prelingual Severe to profound; stable  
DFNB22 OTOA  Prelingual Usually severe to profound; stable 
DFNB23 PCDHlS  Prelingual Severe to profound; stable 
DFNB24 RDX  Prelingual Severe to profound; stable  
DFNB25 GRXCRl  Prelingual Moderate to profound; prog. 
DFNB28 TRIOBP  Prelingual Severe to profound; stable  
DFNB29 CLDN14  Prelingual Severe to profound; stable  
DFNB30 MY03A  Prelingual Severe to profound; stable  
DFNB31 WHRN  Prelingual  
DFNB32/82 GPSM2  Prelingual Severe to profound; stable  
DFNB35 ESRRB  Unknown Severe to profound 
DFNB36 ESPN  Prelingual   
DFNB37 MY06  Prelingual   
DFNB39 HGF  Prelingual  Severe to profound; downsloping 
DFNB49 MARVELD2  Prelingual Moderate to profound; stable 
DFNB53 COL11A2  Prelingual  Severe to profound; stable  
DFNB59 DFNB59  Prelingual  Severe to profound; stable 
DFNB61 SLC26AS  Prelingual  Severe to profound; stable  
DFNB63 RTOMT  Prelingual  Severe to profound; stable  
DFNB67 LHFPLS  Prelingual  Severe to profound; stable  
DFNB73 BSND  Prelingual  Severe to profound; stable  
DFNB76 SYNE4  Prelingual High frequency; progressive
DFNB77 LOXHDl  Postlingual Moderate to profound; prog. 
DFNB79 TPRN  Prelingual  Severe to profound; stable
DFNB84 PTPRQ Prelingual Moderate to profound; prog

Adapted from Van Camp & Smith (2010]
See Deafness, Autosomal Recessive: Phenotypic Series to view genes associated with this phenotype in OMIM 

  1. Prelingual deafness also includes congenital deafness.
  2. The onset of  DFNB8 hearing loss is postlingual (age 10-12 years), while the onset of DFNB O hearing loss is prelingual (congenital). This phenotypic difference reflects a genotypic difference - the DFNB8-causing variant is a splice site variant, suggesting that inefficient splicing is associated with a reduced amount of normal protein that is sufficient to prevent prelingual deafness but not sufficient to prevent eventual hearing loss.

Table  3. Clinical  Manifestations  and  Molecular  Genetics  of  X-Linked  Nonsyndromic Hearing Impairment

Locus Gene Onset Type and Degree Frequencies
DFNXl (DFN2) PRPSl Postlingual Progressive sensorineural; severe to profound All
DFNX2 (DFN3) POU3F4 Prelingual Progressive mixed; variable, but progresses to profound All
DFNX4 (DFN6) SMPX Postlingual Progressive, sensorineural; mild to profound All

Adapted from Van Camp & Smith (2010]
See Deafness, X-linked: Phenotypic Series to view genes associated with this phenotype in OMIM.

Cochlear Implants
Busi et al. (2015) provided the following information regarding cochlear implants for pediatric patients. The World Health Organization (n.d.) defines the pediatric population as individuals under 20 years old.
Cochlear implants: https://www.hindawi.com/journals/bmri/2015/696281/

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.

Related Policies
70105  Cochlear Implant 
204102 Whole Exome Sequencing  

Policy 

  1. Genetic counseling is MEDICALLY NECESSARY and recommended in patients considered for genetic testing for nonsyndromic hereditary hearing loss.
  2. Genetic testing for the two most common mutations for nonsyndromic hereditary hearing loss (GJB2 and GJB6) is considered MEDICALLY NECESSARY in individuals to confirm the diagnosis of hereditary hearing loss where other causes of nonsyndromic acquired hearing loss (infection, injury, age-related) have been excluded.
  3. Genetic testing using gene panel tests or NGS technologies for additional hereditary hearing loss-related mutations is considered MEDICALLY NECESSARY if ALL of the following are met:
    • ONLY AFTER initial testing for common mutations (GJB2 and GJB6) is negative
    • Syndrome is not suspected based on individual’s clinical presentation
  4. Genetic testing is considered MEDICALLY NECESSARY for individuals with a known familial mutation variant.
  5. Genetic testing using gene panel tests or NGS technologies for suspected syndromic hearing loss is considered MEDICALLY NECESSARY 
  6. Genetic testing for hereditary hearing loss-related mutations is INVESTIGATIONAL 
    • If more than once per lifetime
    • For all other situations, including, but not limited to, testing in individuals without hearing loss

Benefit Application
BlueCard®/National Account Issues
Some plans may have contract or benefit exclusions for genetic testing.

Recommendations from specialty societies such as the American College of Medical Genetics 4 and the Joint Committee on Infant Hearing5 indicate that testing of the index case (proband) with hereditary hearing loss be performed so that carrier testing in unaffected parents can focus on the mutation found in the affected family member. However, coverage for testing of the affected index case (proband) is dependent on contract benefit language.

Specific contract language must be reviewed and considered when determining coverage for testing. In some cases, coverage for testing the index case may be available through the contract that covers the unaffected, at-risk individual who will benefit from knowing the results of the genetic test. 

Rationale 
In 2014, the American College of Medical Genetics and Genomics issued the following guidelines for the clinical evaluation and diagnosis of hearing loss. 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, ACMG recommends that a tiered diagnostic approach should be implemented.

  • Pretest genetic counseling should be provided, and, with patient's informed consent, genetic testing should be ordered.
  • 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
  • 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 DFNBl-related hearing loss (due to mutations in GJB2 and adjacent deletions in GJB6).
  • 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, WES or WGS may be considered. Because several tests are clinically available, the clinician must be aware of the genes 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. It should be noted that the cost of these new genetic sequencing technologies is decreasing so rapidly that a tiered approach to testing may soon no longer be cost-effective. In particular, for large sequencing panels targeted toward hearing loss­-related genes, it may, in some cases, already be more cost-effective to use NGS technologies as the initial test in the evaluation of hearing loss. However, issues related to genomic testing, such as the likelihood of incidental findings, will have to be addressed.
  • 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.
  • If genetic testing fails to identify an etiology for a patient's hearing loss, the possibility of a genetic or acquired etiology remains. This point must be emphasized, because it can be misunderstood by clinicians and by patients and their families. For interested  patients  and  families,  further  genetic  testing may  be  pursued  on  a research basis. 

In 2007, the Joint Commission on Infant Hearing recommended that evaluation of infants with confirmed hearing loss 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.

References 

  1. American Academy of Pediatr ics (2007). Joint Committee on Infant Hearing Year 2007 Position Statement: Principles and Guidelines for Early Hearing Detection and Intervention Programs. Pediatrics, 120(4), 898-921. 
  2. American College of Medical Genetics and Genomics (2014). American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss.Genetics in medicine,16(4), 347-355. 
  3. Busi, M., Rosignoli, M.,Castiglione, A., ... Martini, A. Cochlear implant outcomes and genetic mutations in children with ear and brain anomalies.BioMed Research International, vol. 2015, Article ID 696281,19 pages,2015. doi: 0.1155/2015/696281 
  4. Phillips, LL.; Bitner-Glindzicz, M.; Lench, N.; Steel, K.P.; Langford, C.; Dawson, S.J.; Davis, A.; Simpson, S.;& Packer, C. (2013). The future role of genetic screening to detect newborns at risk of childhood-onset hearing loss. International Journal af Audiology. 52: 124-133. 
  5. Smith RJH, Shearer AE, Hildebrand MS, et al. Deafness and Heredita ry Hearing Loss Overview. 1999 Feb 14 [Updated 2014 Jan 9]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. Gene Reviewse [Internet] . Seattle (WA): University of Washington, Seattle; 1993-2017. Available from :https://www.ncbi .nlm.nih.gov/books/NBK1434/ 
  6. World Health Organization. (n.d.) Adolescent health. Retrieved April 10, 2017, from http://www.who.int/topics/ado lescent  health/en/

Coding Section

Codes Number 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 (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 
  96040  Medical genetics and genetic counseling services, each 30 minutes face-to-face with patient/family 
  S0265  Genetic counseling under physician supervision, each 15 minutes 
  S3844  DNA analysis of the connexin 26 gene (GJB2) for susceptibility to congenital, profound deafness  
ICD-9-CM Diagnosis 389.00-389.08 Conductive hearing loss code range
  389.10-389.18 Sensorineural hearing loss code range
  389.20-389.22 Mixed conductive and sensorineural hearing loss code range
 

389.8

Other specified form of hearing loss
  V19.2 Family history of deafness or hearing loss
  V26.31 Testing of female genetic disease carrier status
  V2634 Testing of male for genetic disease carrier status
  V82.71 Screening for genetic disease carrier status
  V84.89 Genetic susceptibility to other disease
ICD-10-CM (effective 10/01/15) H90.0-H91.8X9 Conductive and sensorineural hearing loss code range
  H90.3  Sensorineural hearing loss, bilateral 
  H90.41  Sensorineural hearing loss, unilateral, right ear, with unrestricted hearing on the contralateral side 
  H90.42  Sensorineural hearing loss, unilateral, left ear, with unrestricted hearing on the contralateral side 
  H90.5  Unspecified sensorineural hearing loss 
  H90.6  Mixed conductive and sensorineural hearing loss, bilateral 
  H90.71  Mixed conductive and sensorineural hearing loss, unilateral, right ear, with unrestricted hearing on the contralateral side 
  H90.72  Mixed conductive and sensorineural hearing loss, unilateral, left ear, with unrestricted hearing on the contralateral side 
  H91.8X1 Other specified hearing loss, right ear
  H91.8X2  Other specified hearing loss, left ear
  H91.8X3  Other specified hearing loss, bilateral
  Z13.71  Encounter for nonprocreative screening for Genetic Disease carrier status 
  Z14.8 Genetic carrier of other disease
  Z15.89 Genetic susceptibility to other disease
  Z31.430 Encounter of female for testing for genetic disease carrier status for procreative management
  Z31.440 Encounter of male for testing for genetic disease carrier status for procreative management
  Z82.2 Family history of deafness and hearing loss
ICD-10-PCS (effective 10/01/15)   Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory test.
Type of Service    
Place of Service    

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

07/12/2019 

Annual review. Updating title to remove "nonsyndromic," updating verbiage in criteria for implementation and clarity, adding verbiage regarding gene panel tests/NGS technologies for suspected syndromic hearing loss. 

06/19/2019 

Interim review. "Genetic counseling is recommended" is replacing "Genetic counseling is Medically Necessary." No other changes made. 

07/26/2018 

Annual review, adding coverage statement regarding genetic counseling, reformatting some policy language for clarity. Updating coding. 

06/21/2017

Interim review, updating title, background, description, references, rationale and policy. 

04/25/2017 

Updated category to Laboratory. No other changes.

12/05/2016 

Annual review, no change to policy intent. 

11/12/2015 

Annual review, no change to policy intent. Updated background, description, regulatory status, guidelines, rationale and references. Added appendix 1.

12/02/2014

New Policy


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