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