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This order guide is powered by PLUGS®Order Guide: Hearing Loss
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:
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:
General utilization management interventions & considerations
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.
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.
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.
Recommendations for responsible coordination of hearing loss gene panels
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:
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.