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 [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
Genetic Testing for Hereditary Hearing Loss
Introduction
Hearing loss 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.
Genetic Testing Medical Necessity
Variants in hereditary hearing loss genes
Preconception genetic testing for hereditary hearing loss variants
Genetic testing for hereditary hearing loss genes (GJB2, GJB6, and other hereditary hearing loss-related genes) in individuals with suspected hearing loss in order to confirm the diagnosis of hereditary hearing loss (see Related Information) may be considered medically necessary.
Preconception genetic testing (carrier testing) for hereditary hearing loss gene (GJB2, GJB6, and other 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
Genetic Testing Investigational
Variants in hereditary hearing loss genes
Related Information
Hereditary hearing loss can be classified as syndromic or nonsyndromic. 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 may cause both syndromic and nonsyndromic hearing loss. Given this overlap, the policy focuses on genetic testing for hereditary hearing loss more generally.
In addition to pathogenic variants in the GJB6 and GJB2 genes, there are many less common pathogenic variants found in other genes. They include: 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 syndromic or nonsyndromic 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 heterogeneity in genetic causes of hearing loss, these 2 strategies may be considered reasonably equivalent.
Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.
The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.
Table 1. Nomenclature to Report on Variants Found in DNA
Previous Updated Definition
Mutation Disease-associated variant Disease-associated change in the DNA sequence
Variant Change in the DNA sequence
Familial variant Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives
Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification Definition
Pathogenic Disease-causing change in the DNA sequence
Likely pathogenic Likely disease-causing change in the DNA sequence
Variant Classification Definition
Variant of uncertain significance Change in DNA sequence with uncertain effects on disease
Likely benign Likely benign change in the DNA sequence
Benign Benign change in the DNA sequence
ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology
Genetic Counseling
Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Genetic Testing for the Diagnosis of Inherited Peripheral Neuropathies
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