This order guide is powered by PLUGS®

Order Guide: Hearing Loss

Background

The intent of this document is to provide guidance on the optimal coordination of genetic testing for hearing loss. The genetics of hearing loss is complex and evolving, making the selection of an appropriate genetic test for hearing loss challenging. The following variables should be considered prior to ordering a hearing loss gene panel, and when in doubt, consider reviewing the order with an internal expert/manager/leader.

Hearing loss is the most common birth defect; approximately 1 in 500 newborns have bilateral permanent sensorineural hearing loss ≥40 dB. The most common environmental, non-genetic cause of congenital hearing loss is congenital cytomegalovirus (CMV) infection. The diagnosis of in utero CMV exposure can be assessed through qualitative PCR analysis of the newborn blood spot. The majority of prelingual deafness is genetic, typically follows an autosomal recessive inheritance pattern, and is non-syndromic. However, genetic forms of hearing loss can follow autosomal, X-linked, or mitochondrial inheritance patterns. Approximately 50% of autosomal recessive non-syndromic hearing loss can be attributed to mutations in GJB2 (encodes the protein connexin 26) and GJB6 (encodes the protein connexin 30) (nonsyndromic hearing loss and deafness (DFNB1)). Approximately 1 in 33 individuals in the general population is a carrier for a recessive deafness-causing GJB2 mutation. Over 400 genetic syndromes that include hearing loss have been described, including two of the most common: Pendred syndrome (associated with pathogenic variants in SLC26A4) and Usher syndrome (associated with pathogenic variants in multiple genes). Available hearing loss gene panels include analysis by next-generation sequencing (NGS), deletion and duplication testing, and targeted sequencing of common variants of many genes associated with both non-syndromic and syndromic hearing loss.

Although the availability and accessibility of gene panels are increasing, the impact on clinical management is changing more slowly and still rests largely on patient findings from examinations, history, and other investigations. Given the genetic heterogeneity of hearing loss, selecting a comprehensive testing approach such as a hearing loss gene panel may be the optimal test once obvious conditions have been excluded.

Genetic testing in individuals with hearing loss is typically pursued for the following reasons:

• To guide medical interventions (e.g. medications, other treatment s or surveillance)
• To avoid unnecessary testing (e.g. repeated blood tests, MRIs, invasive biopsies, intracranial electrodes)
• To inform prognosis (e.g. anticipatory guidance)
• To provide information regarding recurrence risk (guide reproductive planning)
• To end the diagnostic odyssey

back to top

There are numerous genetic tests that help determine the underlying molecular etiology of hearing loss in an individual. Hearing loss genetic testing typically consists of sequencing (e.g., Sanger sequencing or DNA-enrichment methods and massively parallel nucleotide sequencing) and quantitative deletion/duplication (e.g., multiple ligation-dependent probe amplification (MLPA), quantitative PCR, or array comparative genomic hybridization) methodologies to identify disease-associated, protein-coding variants in genes associated with this clinical spectrum. Selecting the optimal test depends on careful review of personal and family medical histories (e.g. age at onset, unilateral vs. bilateral, inheritance pattern in a family), physical exam (e.g. screen for associated comorbidities such as dysmorphic features, intellectual disability, birth defects), and imaging (e.g. CT scan of the internal auditory canal).

These evaluations might suggest a syndrome associated with variants in a specific gene or set of genes (e.g. findings of cysts in the neck and kidney abnormalities in addition to hearing loss would be consistent with Branchio-oto-renal syndrome, most likely to be caused by sequencing variants in the EYA1 gene); targeted testing of an individual gene or small set of genes (including both sequencing and testing for deletions and duplications within the gene) is likely to be the most appropriate option for such patients. If the clinical features do not point to a particular syndrome or molecular etiology, a panel that includes sequencing and deletion or duplication testing for several genes associated with hearing loss is likely the best first test.

The following questions provide a helpful framework when considering ordering a hearing loss gene panel and its appropriateness for the individual:

• Does the individual have isolated hearing loss or hearing loss plus other clinical features?
  Depending on whether the individual has isolated hearing loss or hearing loss as part of a suspected syndrome, a single-gene test, chromosomal microarray, or targeted panel may have sufficient diagnostic yield to be a more appropriate first test rather than a large hearing loss gene panel. A referral to, or consult with an expert, such as a geneticist, should be considered if there are questions about whether the individual has features suggestive of a genetic syndrome.
• Has the optimal gene panel been selected based on the individual’s features?
  When considering a hearing loss gene panel, size matters. The more genes included in the panel, the greater the likelihood of detecting variants of uncertain clinical significance. Many panels include genes that have loose associations with hearing loss so there is also the possibility of an incidental result that may be unrelated to the primary reason for testing. Because of these challenges, thoughtful panel selection is strongly recommended and panels with >120 genes should be approached with caution.
• Is there a specific medical intervention that is being considered?
  Certain interventions may be indicated or contraindicated based on genetic findings. For example, hearing aids may be considered for patients with Usher syndrome type II, but are generally an unsuccessful intervention for patients with Usher syndrome type I.
• Are there multiple individuals in the family with similar clinical features?
  Ascertaining likely inheritance patterns for the family’s hearing loss can help identify probable candidate genes for analysis and testing one individual may benefit many family members. Furthermore, testing many similarly affected individuals may yield more informative results. Once a familial pathogenic variant is detected in one family member, less expensive targeted familial variant testing can typically be offered to appropriate family members instead of full gene sequencing or panel testing.
• What is the benefit of pursuing testing now versus deferring until later?
  Consider that new genes are being discovered at a rapid pace requiring laboratories to frequently review and update gene panels; there will be improved understanding of the variants discovered in known genes and gene-gene interactions. Symptoms and family history may evolve to guide more targeted testing and the cost of testing will likely decrease. In addition, available treatment options may increase.
• Is there suspicion for a novel condition/gene?
  If testing is being pursued to discover a previously unreported cause of a hearing loss condition, enrollment in a research study may be more appropriate.

• When there has been no pre-test counseling for the individual (or legal guardian) regarding risks, benefits, and potential out of pocket costs of the genetic testing.
• When the order is requested by a provider who may not have the appropriate training/expertise to select the optimal test and/or interpret the results. Generally, hearing loss gene panel testing is best coordinated by an otolaryngologist, geneticist, or genetic counselor.

back to top

There are a variety of utilization management (UM) tools that can support appropriate ordering of genetic testing for hearing loss. In addition, each case is unique and will require a balanced consideration of factors unique to genetic testing for hearing loss.

Genetic testing for hearing loss is well-suited for strong UM interventions, including formularies, requirement for high-level approval and privileging.

• Establish a formulary for hearing loss genetic tests to limit ordering to a defined reference laboratory (or set of laboratories) to ensure quality of the test and improve ease of test coordination/logistics. This may also help with negotiating the best price.
• Develop practice parameters with input from experts (e.g. otolaryngologists, geneticists), including guidelines for evaluation and screening, testing algorithms, and a requirement for pre-test counseling with a genetic counselor.
• Require that requests for hearing loss gene panels be reviewed by an expert (pathologist or laboratory genetic counselor) prior to approval.
• Privilege hearing loss gene panel ordering to the experts. Due to the complex nature of this testing, many institutions privilege this test to geneticists or otolaryngologists only.

Set clear expectations for providers regarding the approach to genetic testing for hearing loss and availability of guidelines. Providers may feel that the patient came to them for evaluation, and hearing loss gene panels are a novel but necessary “tool”, so if a test isn’t ordered, they haven’t done their job. Similarly, it is critical for providers to set clear expectations for the patient or family, particularly if there are limits placed on when and how hearing loss gene testing can be ordered and the complexity of multiple tiers of the testing approach.

• Reflex testing options: In some cases, it is more efficient and cost-effective to pursue a reflexive testing approach, starting with single-gene analysis or newborn blood spot screening for CMV. If negative, a hearing loss gene panel could be considered. Some reference laboratories have the option of running the whole exome, but masking the majority of genes and only reporting on hearing loss genes of interest. If this analysis is negative, there may be an option to reflex to the whole exome.
• Size of the panel: a balance must be achieved, likely on a case-by-case basis between a broad approach (test lots of genes regardless of clinical presentation, increased risk of variants) and a targeted panel based on phenotype (risk of not finding an answer with the first test)
• Family member testing options: It is advantageous to be able to test family members to clarify the significance of uncertain variants. Some reference labs perform this targeted familial variant testing at no charge and can perform the testing using saliva or buccal specimens. Other reference labs charge a per variant fee, which can be costly if many variants are identified and warrant further investigation. When selecting the optimal reference lab/test for a hearing loss gene panel, it’s critical to consider the charges and logistics of familial variant testing.
• Panel updates & variant re-interpretation: Some reference labs have policies regarding re-analysis of variants (e.g. ad-hoc, systematic at time intervals, etc). Given the rapid evolution of knowledge, there will be a need for reinterpretation and for laboratories to be nimble in expanding panels to include new genes. When considering a reference lab, inquire about how genes are included on panels and how panels are kept up to date.

Conversations regarding optimal hearing loss gene panel selection and medical necessity of testing for insurance coverage can be strengthened by examples of how hearing loss-related genetic variants could be impactful. Clarification of effects on clinical management, examples of potential clinical validity and clinical utility for diagnostic testing in an affected individual, and examples of potential clinical validity and clinical utility for predictive testing in an unaffected relative of an affected individual who tests positive can help maximize the likelihood of insurance coverage.

back to top

Once a hearing loss gene panel has been established as the most appropriate test, the following recommendations are suggested as a responsible approach to test coordination:

• Pre-test counseling to provide clear information regarding the benefits, limitations and results of the gene panel. The counseling approach should be tailored to the individual; the focus of counseling might differ depending on whether it involves a teenager with hearing loss, the parents of a newborn with congenital hearing loss, or an at-risk family member.
  Clear documentation of medical rationale and necessity of the hearing loss gene panel, combined with insurance preauthorization for the testing to protect the patient/institution from avoidable financial liability.
• Results communication plan established at time of test coordination, to include post-test counseling discussion. The possibility of identifying a variant of uncertain clinical significance may be high and the family should be prepared for the potential need to test other family members to help better understand the patient’s results.

back to top

Alasti F, Van Camp G, Smith RJH. Pendred Syndrome/DFNB4. 1998 Sep 28 [Updated 2014 May 29]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1467/

American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss. (2014). Genetics in Medicine, 16(4), 347. Baldwin EE, Boudreault P, Fox M, Sinsheimer JS, Palmer CG. Effect of pre-test genetic counseling for deaf adults on knowledge of genetic testing. J Genet Couns 2012;21:256–272. Kochhar A, Hildebrand MS, Smith RJ. Clinical aspects of hereditary hearing loss. Genet Med 2007;9:393–408.

Lentz J, Keats B. Usher Syndrome Type II. 1999 Dec 10 [Updated 2016 Jul 21]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1341/

Lentz J, Keats BJB. Usher Syndrome Type I. 1999 Dec 10 [Updated 2016 May 19]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1265/ Pandya A, Arnos KS. Genetic evaluation and counseling in the context of early hearing detection and intervention. Semin Hear 2006;27:205–212.

Pandya A. Nonsyndromic Hearing Loss and Deafness, Mitochondrial. 22 October 2004 [updated 21 April 2011]. In: Pagon RA, Adam MP, Bird TD, et al. (eds). GeneReviews [Internet] University of Washington: Seattle, WA, 1993–2014. http://www-ncbi-nlm-nih-gov.offcampus.lib.washington.edu/books/NBK1422. Accessed 7 February 2014.

Smith RJH, Shearer AE, Hildebrand MS, et al. Deafness and Hereditary Hearing Loss Overview. 1999 Feb 14 [Updated 2014 Jan 9]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1434/

Smith RJH. Branchiootorenal Spectrum Disorders. GeneReviews [serial online] 1993; PMID:20301554. University of Washington, Seattle, WA. http://www-ncbi-nlm-nih-gov.offcampus.lib.washington.edu/books/NBK1380. Accessed 26 November 2013.

Tranebjaerg L, Samson RA, Green GE. Jervell and Lange-Nielsen Syndrome. GeneReviews [serial online] 2010; PMID:20301579. University of Washington, Seattle, WA. http://www-ncbi-nlm-nih-gov.offcampus.lib.washington.edu/books/NBK1405. Accessed 15 June 2012.